Novel compounds

ABSTRACT

The present invention relates to compounds, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of RIP2 kinase, including degrading RIP2 kinase, the treatment of diseases and conditions mediated by the RIP2 kinase, in particular for the treatment of inflammatory diseases or conditions.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions, combinationsand medicaments containing said compounds and processes for theirpreparation. The invention also relates to the use of said compounds,combinations, compositions and medicaments, for example as inhibitors ofthe activity of RIP2 kinase, including degrading RIP2 kinase, thetreatment of diseases and conditions mediated by RIP2 kinase, inparticular for the treatment of inflammatory diseases or conditions

BACKGROUND OF THE INVENTION

Receptor interacting protein-2 (RIP2) kinase, which is also referred toas CARD3, RICK, CARDIAK, or RIPK2, is a TKL family serine/threonineprotein kinase involved in innate immune signaling. RIP2 kinase iscomposed of an N-terminal kinase domain and a C-terminalcaspase-recruitment domain (CARD) linked via an intermediate (IM) region((1998) J Biol. Chem. 273, 12296-12300; (1998) Current Biology 8,885-889; and (1998) J Bio/Chem. 273, 16968-16975). The CARD domain ofRIP2 kinase mediates interaction with other CARD-containing proteins,such as NODI and NOD2 ((2000) J Biol Chem. 275, 27823-27831 and (2001)EMBO reports 2, 736-742). NODI and NOD2 are cytoplasmic receptors whichplay a key role in innate immune surveillance. They recognize both grampositive and gram negative bacterial pathogens and are activated byspecific peptidoglycan motifs, diaminopimelic acid (i.e., DAP) andmuramyl dipeptide (MDP), respectively ((2007) J Immunol 178, 2380-2386).

Following activation, RIP2 kinase associates with NODI or NOD2 andappears to function principally as a molecular scaffold to bringtogether other kinases (TAKI, IKKα/β/γ) involved in NF-κB andmitogen-activated protein kinase activation ((2006) Nature ReviewsImmunology 6, 9-20). RIP2 kinase undergoes a K63-linkedpolyubiquitination on lysine-209 which facilitates TAKI recruitment((2008) EMBO Journal 27, 373-383). This post-translational modificationis required for signaling as mutation of this residue prevents NOD 1/2mediated NF-kB activation. RIP2 kinase also undergoesautophosphorylation on serine-176, and possibly other residues ((2006)Cellular Signalling 18, 2223-2229). Studies using kinase dead mutants(K47A) and non-selective small molecule inhibitors have demonstratedthat RIP2 kinase activity is important for regulating the stability ofRIP2 kinase expression and signaling ((2007) Biochem J 404, 179-190 and(2009) J Bioi. Chem. 284, 19183-19188).

Dysregulation of RIP2-dependent signaling has been linked to autoinflammatory diseases. Gain-of-function mutations in the NACHT-domain ofNOD2 cause Blau Syndrome, early-onset sarcoidosis, a pediatricgranulomateous disease characterized by uveitis, dermatitis, andarthritis ((2001) Nature Genetics 29, 19-20; (2005) Journal ofRheumatology 32, 373-375; (2005) Current Rheumatology Reports 7,427-433; (2005) Blood 105, 1195-1197; (2005) European Journal of HumanGenetics 13, 742-747; (2006) American Journal of Ophthalmology 142,1089-1092; (2006) Arthritis & Rheumatism 54, 3337-3344; (2009) Arthritis& Rheumatism 60, 1797-1803; and (2010) Rheumatology 49, 194-196).Mutations in the LRR-domain of NOD2 have been strongly linked tosusceptibility to Crohn's Disease ((2002) Am. J Hum. Genet. 70, 845-857;(2004) European Journal of Human Genetics 12, 206-212; (2008) MucosalImmunology (2008) 1 (Suppll), 55-59. 1, S5-S9; (2008) Inflammatory BowelDiseases 14, 295-302; (2008) Experimental Dermatology 17, 1057-1058;(2008) British Medical Bulletin 87, 17-30; (2009) Inflammatory BowelDiseases 15, 1145-1154 and (2009) Microbes and Infection 11, 912-918).Mutations in NODI have been associated with asthma ((2005) Hum. Mol.Genet. 14, 935-941) and early-onset and extra-intestinal inflammatorybowel disease ((2005) Hum. Mol. Genet. 14, 1245-1250). Genetic andfunctional studies have also suggested a role for RIP2-dependentsignaling in a variety of other granulomateous disorders, such assarcoidosis ((2009) Journal of Clinical Immunology 29, 78-89 and (2006)Sarcoidosis Vasculitis and Diffuse Lung Diseases 23, 23-29) and Wegner'sGranulomatosis ((2009) Diagnostic Pathology 4, 23).

A potent, selective, small molecule inhibitor of RIP2 kinase activitywould block RIP2-dependent pro-inflammatory signaling and therebyprovide a therapeutic benefit in auto inflammatory diseasescharacterized by increased and/or dysregulated RIP2 kinase activity.

It would be desirable to investigate other approaches to antagonise theRIP2 kinase.

One approach would be to develop selective RIP2 kinases down regulatorsor degraders that reduce RIP2 expression at either the transcript orprotein level.

Several methods are available for the manipulation of protein levels,including proteolysis targeting chimeric molecules (Protacs) whichcontain a ligand that recognizes the target protein linked to a ligandthat binds to a specific E3 ubiquitin ligase. It would be desirable tohave a small molecule which can simultaneously bind RIP2 kinase and anE3 ubiquitin ligase and which promotes ubiquitination of RIP2 Kinase andleads to its degradation by the Proteosome. One suitable E3 ubiquitinligase is the von Hippel-Lindau tumour suppressor (VHL), see for exampleWO2013/106643.

It would be desirable to identify further ubiquitin ligase bindingmolecules to incorporate into PROTAC molecules.

Inhibitors of Apoptosis (IAP) have been proposed with limited success,see for example Okuhira et al, Cell Death and Disease, 2014, 5,e1513.IAP inhibitors now known which can be of use in their own right asantitumour agents, see for example L. Bai et al./Pharmacology &Therapeutics 144 (2014) 82-95 Apoptosis is one form of programmedcell-death and is a normal cellular process used by multi-cellularorganisms to eliminate damaged or unwanted cells. Apoptosis is a tightlyregulated process and faulty regulation of apoptosis is implicated inmany human diseases, including cancer, autoimmune diseases,inflammation, and neurogenesis (Lowe S. W and Lin 2000 Carcinogenesis21(3), 485-495, Nicholson D. W. 2000, Nature 407 (6805) 810-816, Reed J.C. 2002 Nat Rev Drug Discovery 1(2) 111-121).

IAP inhibitors are disclosed in WO 2014031487 WO 2014047024 whichdescribe linked dimeric compounds. WO 2014055461 describes bivalentcompounds and WO 2008128171 describes IAP inhibitors all with a view totreating disorders associated with apoptosis, particularly cancer.

The present inventors have identified IAP compounds which whenincorporated into PROTACs targeting RIP2 kinase are capable of promotingtarget degradation.

SUMMARY OF THE INVENTION

The present invention provides Protac compounds which modulate RIP2kinase activity including degradation thereof which comprise RIP2 kinaseinhibitors having the following substructure:

wherein X represents N or —CH.

RIP 2 inhibitors with this substructure are disclosed in WO2014/128622,WO20140/43437, WO 2013/025958, WO 2012/122011, WO 2012/021580 and WO2011140442. These applications describe suitable substitutions onequivalent positions to Z, R¹ and R² in the RIP2 binding portiondepicted.

In a first aspect the present invention provides a compound of formula(I):

whereinX represents N or CH;L is a linking group comprising a length of 4-20 atoms in shortestlength,R¹ is H, —SO₂(C₁-C₄)alkyl, —CO(C₁-C₄)alkyl, or (C₁-C₄)alkyl;R² is —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NH₂, or —SO₂NR^(b)R^(c),wherein R^(a) is (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₂)cycloalkyl, 4-7membered heterocycloalkyl, aryl, or heteroaryl, wherein:

said (C₁-C₆)alkyl is optionally substituted by one or two groups eachindependently selected from the group consisting of cyano, hydroxyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₂-C₆)alkoxy, —CO₂H, —CO₂(C₁-C₄)alkyl,—SO₂(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl, 5-6 membered heteroaryl,9-10 membered heteroaryl, 4-7 membered heterocycloalkyl and(phenyl)(C₁-C₄ alkyl)amino-, wherein said (C₃-C₇)cycloalkyl, phenyl,(phenyl)(C₁-C₄ alkyl)amino-, 5-6 membered heteroaryl, 9-10 memberedheteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by1-3 groups each independently selected from the group consisting ofhalogen, —CF₃, hydroxyl, amino, ((C₁-C₄)alkyl)amino-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl and (C₁-C₄)alkoxy,

said (C₃-C₇)cycloalkyl or 4-7 membered heterocycloalkyl is optionallysubstituted by 1-3 groups each independently selected from the groupconsisting of halogen, —CF₃, hydroxyl, amino, ((C₁-C₄)alkyl)amino-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl-, oxo and (C₁-C₄)alkoxy, and

said aryl or heteroaryl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of halogen, —CF₃,hydroxyl, amino, ((C₁-C₄)alkyl)amino-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl- and (C₁-C₄)alkoxy;

R^(b) is (C₁-C₆)alkyl or 4-7 membered heterocycloalkyl, wherein:

said (C₁-C₆)alkyl is optionally substituted by one or two groups eachindependently selected from the group consisting of hydroxyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₂-C₆)alkoxy, —CO₂H, —CO₂(C₁-C₄)alkyl,(C₁-C₄ alkyl)amino-, (C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl, wherein said 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by1-3 groups each independently selected from the group consisting ofhalogen, (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl and (C₁-C₄)alkoxy,

said 4-7 membered heterocycloalkyl is optionally substituted by 1-3groups each independently selected from the group consisting ofhydroxyl, amino, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl-,hydroxy(C₁-C₄)alkyl-, oxo and (C₁-C₄)alkoxy, and

R^(c) is H, (C₁-C₄)alkoxy or (C₁-C₆)alkyl;

or R^(b) and R^(c) taken together with the nitrogen atom to which theyare attached form a 3-7 membered heterocycloalkyl group, optionallycontaining one or two additional ring heteroatoms each independentlyselected from nitrogen and oxygen, wherein said 3-7 memberedheterocycloalkyl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of (C₁-C₄)alkyl,hydroxy, —CO₂H and —CO(C₁-C₄)alkyl; Z is phenyl or aryl(C₁-C₄)alkyl-,wherein in the phenyl group or the aryl moiety of the aryl(C₁-C₄)alkyl-group is substituted by R⁴, R⁵, R⁶ and R⁷, wherein:

R⁴ is H, halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, oraminocarbonyl, wherein the phenyl moiety of said phenoxy orphenyl(C₁-C₄)alkoxy- is optionally substituted by 1-3 substituents eachindependently selected from the group consisting of halogen, —CF₃,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; and

each of R⁵, R⁶ and R⁷ is independently selected from the groupconsisting of H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; or

Z is phenyl or pyridyl, substituted by R⁸, R⁹ and R¹⁰, wherein:

R⁸ and R⁹ are located on adjacent atoms and taken together with theatoms to which they are attached form a 5-membered ring containing 1, 2or 3 heteroatoms each independently selected from N, O and S, which5-membered ring is substituted by R¹¹;

wherein one of R¹⁰ or R¹¹ is H, halogen, cyano, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, or aminocarbonyl, where the phenyl moiety of saidphenoxy or phenyl(C₁-C₄)alkoxy is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy; and

the other of R¹⁰ or R¹¹ is H, hydroxyl, halogen, —CF₃,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl or (C₁-C₄)alkoxy; or

Z is pyrazolyl, having the formula:

wherein:

R¹² is H, methyl or hydroxymethyl;

R¹³ is methyl, trifluoromethyl or hydroxymethyl;

R¹⁴ is H, OH, or (C₁-C₃)alkyl; or

R¹² and R¹³, taken together with the atoms to which they are attached,form a 6-membered ring substituted by R¹⁵ and R¹⁶, wherein the6-membered ring optionally contains 1 nitrogen atom;

wherein R¹⁵ and R¹⁶ are each independently selected from the groupconsisting of H, halogen, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, and aminocarbonyl, wherein the phenyl moiety ofsaid phenoxy or phenyl(C₁-C₄)alkoxy is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy;

or a pharmaceutically acceptable salt thereof.

In a further aspect of the present invention, there is provided acompound of formula (I) or a pharmaceutically acceptable salt thereoffor use in therapy.

In a further aspect there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofdiseases conditions mediated by RIP2 Kinase.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and one or more ofpharmaceutically acceptable carriers, diluents and excipients.

In a further aspect of the present invention, there is provided a methodof treating diseases and conditions mediated by the RIP2 Kinase in asubject comprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In a further aspect of the present invention, there is provided the useof a compound of formula (I), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for use in treating diseasesand conditions mediated by the RIP2 Kinase.

In a further aspect there is provided a combination comprising acompound of formula (I), or a pharmaceutically acceptable salt thereofand at least one further therapeutic agent.

In a further aspect there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further therapeutic agent for use in therapy.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further therapeutic agent and one or more ofpharmaceutically acceptable carriers, diluents and excipients.

In a further aspect of the invention there is provided a combinationcomprising compound of formula (I) or a pharmaceutically acceptable saltthereof and at least one further therapeutic agent for use in treatingdiseases and conditions mediated by the RIP2 Kinase.

In a further aspect there is provided a method of treating diseases andconditions mediated by the RIP2 Kinase comprising administering to ahuman in need thereof a therapeutically effective amount of acombination comprising compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agent.

In a further aspect there is provided the use of a combinationcomprising compound of formula (I) or a pharmaceutically acceptable saltthereof and at least one further therapeutic agent in the manufacture ofa medicament for treating diseases and conditions mediated by RIP2Kinase.

In a further aspect there is provided a method of degrading RIP2 kinasecomprising administering to a human in need thereof a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “a compound of the invention” includes all solvates,complexes, polymorphs, radiolabelled derivatives, stereoisomers andoptical isomers of the compounds of formula (I) and salts thereof.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and dosage forms which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of human beings and animals without excessive toxicity,irritation, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The compounds of the invention may exist in solid or liquid form. Insolid form, compound of the invention may exist in a continuum of solidstates ranging from fully amorphous to fully crystalline. The term‘amorphous’ refers to a state in which the material lacks long rangeorder at the molecular level and, depending upon the temperature, mayexhibit the physical properties of a solid or a liquid. Typically suchmaterials do not give distinctive X-ray diffraction patterns and, whileexhibiting the properties of a solid, are more formally described as aliquid. Upon heating, a change from solid to liquid properties occurswhich is characterized by a change of state, typically second order(‘glass transition’). The term ‘crystalline’ refers to a solid phase inwhich the material has a regular ordered internal structure at themolecular level and gives a distinctive X-ray diffraction pattern withdefined peaks. Such materials when heated sufficiently will also exhibitthe properties of a liquid, but the change from solid to liquid ischaracterized by a phase change, typically first order (‘meltingpoint’).

The compound of formula (I) may exist in solvated and unsolvated forms.As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt) and a solvent. Such solvents for the purpose ofthe invention may not interfere with the biological activity of thesolute. The skilled artisan will appreciate that pharmaceuticallyacceptable solvates may be formed for crystalline compounds whereinsolvent molecules are incorporated into the crystalline lattice duringcrystallization. The incorporated solvent molecules may be watermolecules or non-aqueous such as ethanol, isopropanol, DMSO, aceticacid, ethanolamine, and ethyl acetate molecules. Crystalline latticeincorporated with water molecules are typically referred to as“hydrates”. Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water. The present inventionincludes all such solvates.

The compounds of the invention may have the ability to crystallize inmore than one form, a characteristic, which is known as polymorphism,and it is understood that such polymorphic forms (“polymorphs”) arewithin the scope of the invention. Polymorphism generally can occur as aresponse to changes in temperature or pressure or both and can alsoresult from variations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility and melting point.

It is also noted that the compounds of formula (I) may form tautomers.It is understood that all tautomers and mixtures of tautomers of thecompounds of the present invention are included within the scope of thecompounds of the present invention.

The compound of Formula (I) is a Protac targeting RIP Kinase wherein theRIP2 kinase inhibitor is linked via a linker to a IAP binder.

In one embodiment, the present invention provides a Protac targetingRIP2 kinase which is a compound of Formula (II), (III), or (IV):

Substituents in equivalent positions on the IAP binding moiety may befound described in WO 2014/047024 and WO 2014/055461.

In particular, the definitions of R¹, Z, X and R² in the RIP2 inhibitormoiety in the compounds of formula (II) and (III) are as defined informula (I) above.

The linker is as defined for formula (I) above.

For the IAP binding moiety, in formula (II) and (III)

R¹ and R² are independently optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted arylalkyl, optionally substituted aryl, or

R¹ and R² are independently optionally substituted thioalkyl wherein thesubstituents attached to the S atom of the thioalkyl are optionallysubstituted alkyl, optionally substituted branched alkyl, optionallysubstituted heterocyclyl, —(CH2)vCOR20, —CH2CHR₂₁COR₂₂ or —CH₂R₂₃.Wherein

v-1-3,

R₂₀ and R₂₂ are independently selected from OH, NR₂₄ R₂₅ or OR₂₆,

R₂₁ is NR₂₄R₂₅,

R23 is optionally substituted aryl or optionally substitutedheterocyclyl, where the optional substituents include alkyl and halogen,

R₂₄ is hydrogen or optionally substituted alkyl,

R₂₅ is hydrogen, optionally substituted alkyl, optionally substitutedbranched alkyl, optionally substituted arylalkyl, optionally substitutedheterocyclyl, —CH2(OCH₂CH₂O)_(m)CH₃, or a polyamine chain,

R₂₆ is optionally substituted alkyl,

w=1-8,

Where the optional substituents are OH, halogen or NH₂;R³ and R⁴ are independently optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted arylalkoxy, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted heteroarylalkyl or optionally substituted hetercycloalkyl,wherein the substitutents are alkyl, halogen or OH;

R₅, R⁶, R⁷ and R⁸ are independently hydrogen, optionally substitutedalkyl or optionally substituted cycloalkyl;

R⁹ is hydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl or CO alkyl;

or a pharmaceutically acceptable salt thereof.

In particular, the definitions of R¹, Z, X and R² in the RIP2 inhibitormoiety in the compounds of formula (IV) are as defined in formula (I)above.

The linker is as defined for formula (I) above.

For the IAP binding moiety, in formula (IV)

R is selected from the group consisting of

wherein ring A is C₄-8 aliphatic ring,

wherein the B ring is aryl or nitrogen atom-containing heteroaryl andthe B rings are optionally substituted;or a pharmaceutically acceptable salt thereof.

In one aspect ring B is phenyl, napthyl, pyridinyl, pyrazinyl orpyrimidinyl.

In one aspect the linker is a straight chain alkyline group of 4-20carbon atoms wherein one or more carbo atoms one replaced by a groupeach independently selected from —O—, —NH—, —N(CH₃), —CO—, piperridine,piperazine, pyrimidine, pyridine, phenyl

In one aspect in compounds of Formula (I), (II), (III), and (IV), thelinker group is a straight chain alkylene group of 4-16 carbon atomswherein one or more carbon atoms are replaced by a group eachindependently selected from

—O—, —NH—, —N(CH₃)—, CO,

In one aspect the linker is (in the direction RIP2 Kinase inhibitor-IAPinhibitor):

—O(CH₂CH₂O)₃₋₄—O(Ch₂Ch₂)₄ OCH₂CONH

wherein X is —O(CH₂CH₂)₀₋₄,—

and Y is —CONH—, —O— or —CO—.

Examples of linkers include—(OCH₂CH₂)₄O——(OCH₂CH₂)₃O——(OCH₂CH₂)₄OCH₂CONH

Compounds of Formula (I) include:

-   (S)-7-(2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,-   (S)-7-(2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((S)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,-   (S)-7-(2-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,-   (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-t    ((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-3-methylbutan-2-yl)pyri-   (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,-   (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-N—((R)-2,3-dihydro-1H-inden-1-yl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide,-   (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1-phenyl    propyl)pyrrolidine-2-carboxamide,-   (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-N-(2,6-difluorophenyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide,-   (2S,4S)-4-(2-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-4-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,-   5-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide,-   2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide-   5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide;-   6-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)nicotinamide;-   2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;-   6-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)nicotinamide;-   5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide;-   2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;-   5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide;-   (2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7    yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,-   2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;-   2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;-   2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;-   (S)-7-((6-(4-((6-(Tert-butylsulfonyl)-4-((4,5-di    methyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-4-yl)oxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;-   (S)-7-((6-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-di    methyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-4-yl)oxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;-   (2S,4S)-4-((2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,-   (2S,4S)-4-((2-(4-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,-   (2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,-   (2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,-   (2S,4S)-4-((2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,-   (2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide-   (2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-N-(2,6-difluorophenyl)-1-((S)-3,3-dimethyl-2-((S)-2    (methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide-   2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;-   5-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide-   (S)-1-((S)-2-(1-(2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-di    methyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide;-   (S)-1-((S)-2-(1-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin    yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-((S)-2-(methylamino)propanamido-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide;-   (5S,8S,10aR)—N-Benzhydryl-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide;-   (5S,8S,10aR)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide;-   (5S,8S,10aR)-3-(5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide;-   (5S,8S,10aR)-3-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide;    and pharmaceutically acceptable salts thereof

The compounds of Formula (I) may be in the form of a salt.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention. For a review on suitable salts see Berge et al, J. Pharm.Sci. 1977, 66, 1-19.

Suitable pharmaceutically acceptable salts can include acid additionsalts.

A pharmaceutically acceptable acid addition salt can be formed byreaction of a compound of formula (I) with a suitable inorganic ororganic acid (such as hydrobromic, hydrochloric, sulfuric, nitric,phosphoric, p-toluenesulfonic, benzenesulfonic, methanesulfonic,ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic),optionally in a suitable solvent such as an organic solvent, to give thesalt which is usually isolated for example by crystallisation andfiltration. A pharmaceutically acceptable acid addition salt of acompound of formula (I) can comprise or be for example a hydrobromide,hydrochloride, sulfate, nitrate, phosphate, p-toluenesulfonate,benzenesulfonate, methanesulfonate, ethanesulfonate,naphthalenesulfonate (e.g. 2-naphthalenesulfonate) salt.

In one aspect the salt is a hydrochloride salt.

Other non-pharmaceutically acceptable salts, e.g. trifluoroacetates, maybe used, for example in the isolation of compounds of the invention, andare included within the scope of this invention.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the compounds of formula (I).

While it is possible that, for use in therapy, the compound of theinvention may be administered as the raw chemical, it is possible topresent the compound of the invention as the active ingredient as apharmaceutical composition. Such compositions can be prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound. Accordingly, the invention further providespharmaceutical compositions comprising a compound of the invention andone or more pharmaceutically acceptable excipients. The excipient(s)must be acceptable in the sense of being compatible with the otheringredients of the composition and not deleterious to the recipientthereof. In accordance with another aspect of the invention there isalso provided a process for the preparation of a pharmaceuticalcomposition including the agent, or pharmaceutically acceptable saltsthereof, with one or more pharmaceutically acceptable excipients. Thepharmaceutical composition can be for use in the treatment and/orprophylaxis of any of the conditions described herein.

Generally, the compound of the invention is administered in apharmaceutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound-administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient, vehicle or carrier. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. Preferred unit dosage compositions are thosecontaining a daily dose or sub-dose, or an appropriate fraction thereof,of an active ingredient. Such unit doses may therefore be administeredonce or more than once a day. Such pharmaceutical compositions may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, inhaled, intranasal, topical (including buccal,sublingual or transdermal), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous or intradermal) route. Suchcompositions may be prepared by any method known in the art of pharmacy,for example by bringing into association the active ingredient with thecarrier(s) or excipient(s).

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert excipient such as ethanol,glycerol, water and the like. Powders are prepared by reducing thecompound to a suitable fine size and mixing with a similarly preparedpharmaceutical excipient such as an edible carbohydrate, as, forexample, starch or mannitol. Flavouring, preservative, dispersing andcolouring agent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Excipients including glidants andlubricants such as colloidal silica, talc, magnesium stearate, calciumstearate or solid polyethylene glycol can be added to the powder mixturebefore the filling operation. A disintegrating or solubilizing agentsuch as agar-agar, calcium carbonate or sodium carbonate can also beadded to improve the availability of the medicament when the capsule isingested.

Moreover, when desired or necessary, excipients including suitablebinders, glidants, lubricants, sweetening agents, flavours,disintegrating agents and colouring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, suspensions, syrups and elixirs can beprepared in dosage unit form so that a given quantity contains apredetermined amount of the compound. Syrups can be prepared bydissolving the compound in a suitably flavoured aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a non-toxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxy ethylene sorbitol ethers, preservatives, flavoradditive such as peppermint oil or natural sweeteners or saccharin orother artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit compositions for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time.

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the compositions are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical compositions adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for rectal administration may bepresented as suppositories, rectal foams, rectal gels or as enemas.

Dosage forms for nasal or inhaled administration may conveniently beformulated as aerosols, solutions, suspensions drops, gels or drypowders.

Pharmaceutical compositions adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical compositions adapted for parental administration includeaqueous and non-aqueous sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render thecomposition isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

In one aspect the pharmaceutical composition is is suitable for oral orrectal administration for non systemic or local delivery to the GItract, or is formulated for subcutaneous delivery.

A therapeutically effective amount of the agent will depend upon anumber of factors including, for example, the age and weight of thesubject, the precise condition requiring treatment and its severity, thenature of the formulation, and the route of administration, and willultimately be at the discretion of the attendant physician orveterinarian. In particular, the subject to be treated is a mammal,particularly a human.

The agent may be administered in a daily dose. This amount may be givenin a single dose per day or more usually in a number (such as two,three, four, five or six) of sub-doses per day such that the total dailydose is the same.

Suitably, the amount of the compound of the invention administeredaccording to the present invention will be an amount selected from 0.01mg to 1 g per day (calculated as the free or unsalted compound).

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be employed alone or in combination with other therapeuticagents. The compounds of formula (I) and pharmaceutically acceptablesalts thereof and the other pharmaceutically active agent(s) may beadministered together or separately and, when administered separately,administration may occur simultaneously or sequentially, in any order.by any convenient route in separate or combined pharmaceuticalcompositions.

The amounts of the compound(s) of formula (I) or pharmaceuticallyacceptable salt(s) thereof and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect. The compoundsof the present invention and further therapeutic agent(s) may beemployed in combination by administration simultaneously in a unitarypharmaceutical composition including both compounds. Alternatively, thecombination may be administered separately in separate pharmaceuticalcompositions, each including one of the compounds in a sequential mannerwherein, for example, the compound of the invention is administeredfirst and the other second and visa versa. Such sequentialadministration may be close in time (e.g. simultaneously) or remote intime. Furthermore, it does not matter if the compounds are administeredin the same dosage form, e.g. one compound may be administered topicallyand the other compound may be administered orally. Suitably, bothcompounds are administered orally.

The combinations may be presented as a combination kit. By the term“combination kit” “or kit of parts” as used herein is meant thepharmaceutical composition or compositions that are used to administerthe combination according to the invention. When both compounds areadministered simultaneously, the combination kit can contain bothcompounds in a single pharmaceutical composition, such as a tablet, orin separate pharmaceutical compositions. When the compounds are notadministered simultaneously, the combination kit will contain eachcompound in separate pharmaceutical compositions either in a singlepackage or in separate pharmaceutical compositions in separate packages.

The combination kit can also be provided by instruction, such as dosageand administration instructions. Such dosage and administrationinstructions can be of the kind that are provided to a doctor, forexample by a drug product label, or they can be of the kind that areprovided by a doctor, such as instructions to a patient.

When the combination is administered separately in a sequential mannerwherein one is administered first and the other second or vice versa,such sequential administration may be close in time or remote in time.For example, administration of the other agent several minutes toseveral dozen minutes after the administration of the first agent, andadministration of the other agent several hours to several days afterthe administration of the first agent are included, wherein the lapse oftime is not limited. For example, one agent may be administered once aday, and the other agent may be administered 2 or 3 times a day, or oneagent may be administered once a week, and the other agent may beadministered once a day and the like.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredients(s) may be used in the form of salts,for example as alkali metal or amine salts or as acid addition salts, orprodrugs, or as esters, for example lower alkyl esters, or as solvates,for example hydrates, to optimise the activity and/or stability and/orphysical characteristics, such as solubility, of the therapeuticingredient. It will be clear also that, where appropriate, thetherapeutic ingredients may be used in optically pure form.

When combined in the same composition it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the composition and may be formulated foradministration. When formulated separately they may be provided in anyconvenient composition, conveniently, in such a manner as known for suchcompounds in the art.

When the compound of formula (I) is used in combination with a secondtherapeutic agent active against the same disease, condition ordisorder, the dose of each compound may differ from that when thecompound is used alone. Appropriate doses will be readily appreciated bythose skilled in the art.

In one embodiment the mammal in the methods and uses of the presentinvention is a human.

The compounds of the invention may be particularly useful for treatmentof RIP2 kinase-mediated diseases or disorders, particularly inflammatorydisorders.

In one aspect the disease or condition is inflammation. This inventionalso provides a compound of Formula (I), or a salt thereof, particularlya pharmaceutically acceptable salt thereof, for use in therapy. Thisinvention specifically provides for the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, as an activetherapeutic substance in the treatment of a RIP2 kinase-mediated diseaseor disorder, for example the diseases and disorders recited herein; morespecifically, for use in the treatment of a disease mediated byinhibition of RIP2 kinase.

The invention also provides for the use of a compound of Formula (I), ora salt thereof, particularly a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for use in the treatment of a RIP2kinase-mediated disease or disorder, for example the diseases anddisorders recited herein.

In a further aspect there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further therapeutic agent useful in the treatment of adisease mediated by inhibition of RIP2 kinase

In a further aspect there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further therapeutic agent useful in the treatment of adisease mediated by inhibition of RIP2 kinase for use in therapy.

In a further aspect there is provided a combination comprising acompound of formula (I) or pharmaceutically acceptable salt thereof andat least one one further therapeutic agent useful in the treatment ofallergic disease, inflammation or autoimmune disease, for use in thetreatment a disease mediated by inhibition of RIP2 kinase.

In a further aspect there is provided the use of a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof and at least one one further therapeutic agent useful inthe treatment of allergic disease, inflammation or autoimmune disease inthe manufacture of a medicament for the treatment of a disease mediatedby inhibition of RIP2 kinase

In a further aspect there is provided a method of treating allergicdisease, inflammation or autoimmune disease comprising administering toa human in need thereof a therapeutically effective amount of acombination comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and at least one further therapeutic agentuseful in the treatment of a disease mediated by inhibition of RIP2kinase.

In a further aspect there is provided a pharmaceutical compositioncomprising a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and at least one furthertherapeutic agent useful in the treatment of a disease mediated byinhibition of RIP2 kinase and one or more of pharmaceutically acceptableexcipients.

Inflammation represents a group of vascular, cellular and neurologicalresponses to trauma. Inflammation can be characterised as the movementof inflammatory cells such as monocytes, neutrophils and granulocytesinto the tissues. This is usually associated with reduced endothelialbarrier function and oedema into the tissues. Inflammation can beclassified as either acute or chronic. Acute inflammation is the initialresponse of the body to harmful stimuli and is achieved by the increasedmovement of plasma and leukocytes from the blood into the injuredtissues. A cascade of biochemical event propagates and matures theinflammatory response, involving the local vascular system, the immunesystem, and various cells within the injured tissue. Prolongedinflammation, known as chronic inflammation, leads to a progressiveshift in the type of cells which are present at the site of inflammationand is characterised by simultaneous destruction and healing of thetissue from the inflammatory process.

When occurring as part of an immune response to infection or as an acuteresponse to trauma, inflammation can be beneficial and is normallyself-limiting. However, inflammation can be detrimental under variousconditions. This includes the production of excessive inflammation inresponse to infectious agents, which can lead to significant organdamage and death (for example, in the setting of sepsis). Moreover,chronic inflammation is generally deleterious and is at the root ofnumerous chronic diseases, causing severe and irreversible damage totissues. In such settings, the immune response is often directed againstself-tissues (autoimmunity), although chronic responses to foreignentities can also lead to bystander damage to self tissues.

The aim of anti-inflammatory therapy is therefore to reduce thisinflammation, to inhibit autoimmunity when present and to allow for thephysiological process or healing and tissue repair to progress.

The compound of formula (I) may be used to treat inflammation of anytissue and organs of the body, including musculoskeletal inflammation,vascular inflammation, neural inflammation, digestive systeminflammation, ocular inflammation, inflammation of the reproductivesystem, and other inflammation, as exemplified below.

Musculoskeletal inflammation refers to any inflammatory condition of themusculoskeletal system, particularly those conditions affecting skeletaljoints, including joints of the hand, wrist, elbow, shoulder, jaw,spine, neck, hip, knew, ankle, and foot, and conditions affectingtissues connecting muscles to bones such as tendons. Examples ofmusculoskeletal inflammation which may be treated with compounds offormula (I) include arthritis (including, for example, osteoarthritis,rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acuteand chronic infectious arthritis, arthritis associated with gout andpseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis,tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis,myositis, and osteitis (including, for example, Paget's disease,osteitis pubis, and osteitis fibrosa cystic).

Ocular inflammation refers to inflammation of any structure of the eye,including the eye lids. Examples of ocular inflammation which may betreated with the compounds of formula (I) include blepharitis,blepharochalasis, conjunctivitis, dacryoadenitis, keratitis,keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, anduveitis.

Examples of inflammation of the nervous system which may be treated withthe compounds of formula (I) include encephalitis, Guillain-Barresyndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis,myelitis and schizophrenia.

Examples of inflammation of the vasculature or lymphatic system whichmay be treated with the compounds of formula (I) includearthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

Examples of inflammatory conditions of the digestive system which may betreated with the compounds of formula (I) include cholangitis,cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis,inflammatory bowel disease (such as Crohn's disease and ulcerativecolitis), ileitis, and proctitis.

Examples of inflammatory conditions of the reproductive system which maybe treated with the compounds of formula (I) include cervicitis,chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis,orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis,vulvitis, and vulvodynia.

The compound of formula (I) may be used to treat autoimmune conditionshaving an inflammatory component. Such conditions include acutedisseminated alopecia universalise, Behcet's disease, Chagas' disease,chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosingspondylitis, aplastic anemia, hidradenitis suppurativa, autoimmunehepatitis, autoimmune oophoritis, celiac disease, Crohn's disease,diabetes mellitus type 1, giant cell arteritis, goodpasture's syndrome,Grave's disease, Guillain-Barre syndrome, Hashimoto's disease,Henoch-Schönlein purpura, Kawasaki's disease, lupus erythematosus,microscopic colitis, microscopic polyarteritis, mixed connective tissuedisease, multiple sclerosis, myasthenia gravis, opsocionus myoclonussyndrome, optic neuritis, ord's thyroiditis, pemphigus, polyarteritisnodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren'ssyndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmunehaemolytic anemia, interstitial cystitis, lyme disease, morphea,psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

The compound of formula (I) may be used to treat T-cell mediatedhypersensitivity diseases having an inflammatory component. Suchconditions include contact hypersensitivity, contact dermatitis(including that due to poison ivy), uticaria, skin allergies,respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitiveenteropathy (Celliac disease).

Other inflammatory conditions which may be treated with the agentsinclude, for example, appendicitis, dermatitis, dermatomyositis,endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitissuppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis,otitis, pancreatitis, parotitis, percarditis, peritonoitis, pharyngitis,pleuritis, pneumonitis, prostatistis, pyelonephritis, and stomatisi,transplant rejection (involving organs such as kidney, liver, heart,lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel,skin allografts, skin homografts, and heart valve xengrafts, sewrumsickness, and graft vs host disease), acute pancreatitis, chronicpancreatitis, acute respiratory distress syndrome, Sexary's syndrome,congenital adrenal hyperplasis, nonsuppurative thyroiditis,hypercalcemia associated with cancer, pemphigus, bullous dermatitisherpetiformis, severe erythema multiforme, exfoliative dermatitis,seborrheic dermatitis, seasonal or perennial allergic rhinitis,bronchial asthma, contact dermatitis, astopic dermatitis, drughypersensistivity reactions, allergic conjunctivitis, keratitis, herpeszoster ophthalmicus, iritis and oiridocyclitis, chorioretinitis, opticneuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonarytuberculosis chemotherapy, idiopathic thrombocytopenic purpura inadults, secondary thrombocytopenia in adults, acquired (autroimmine)haemolytic anemia, leukaemia and lymphomas in adults, acute leukaemia ofchildhood, regional enteritis, autoimmune vasculitis, multiplesclerosis, chronic obstructive pulmonary disease, solid organ transplantrejection, sepsis. Preferred treatments include treatment of transplantrejection, rheumatoid arthritis, psoriatic arthritis, multiplesclerosis, Type 1 diabetes, asthma, inflammatory bowel disease, systemiclupus erythematosis, psoriasis, chronic obstructive pulmonary disease,and inflammation accompanying infectious conditions (e.g., sepsis).

Treatment of RIP2 kinase-mediated diseases or disorders, or morebroadly, treatment of immune mediated diseases including, but notlimited to, allergic diseases, autoimmune diseases, prevention oftransplant rejection and the like, may be achieved using a compound ofthis invention as a monotherapy, or in dual or multiple combinationtherapy, with or include one or more other therapeutic agents, forexample selected from NSAIDS, corticosteroids, COX-2 inhibitors,cytokine inhibitors, anti-TNF agents, inhibitors oncostatin M,anti-malarials, immunsuppressive and cytostatics.

This invention also provides a compound of Formula (I), or a saltthereof, particularly a pharmaceutically acceptable salt thereof, foruse in therapy. This invention specifically provides for the use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,as an active therapeutic substance in the treatment of a RIP2kinase-mediated disease or disorder, for example the diseases anddisorders recited herein; more specifically, for use in the treatment ofa disease mediated by inhibition of RIP2 kinase.

The invention also provides for the use of a compound of Formula (I), ora salt thereof, particularly a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for use in the treatment of a RIP2kinase-mediated disease or disorder, for example the diseases anddisorders recited herein.

In a further aspect there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further therapeutic agent useful in the treatment of adisease mediated by inhibition of RIP2 kinase

In a further aspect there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further therapeutic agent useful in the treatment of adisease mediated by inhibition of RIP2 kinase for use in therapy.

In a further aspect there is provided a combination comprising acompound of formula (I) or pharmaceutically acceptable salt thereof andat least one one further therapeutic agent useful in the treatment ofallergic disease, inflammation or autoimmune disease, for use in thetreatment a disease mediated by inhibition of RIP2 kinase.

In a further aspect there is provided the use of a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof and at least one one further therapeutic agent useful inthe treatment of allergic disease, inflammation or autoimmune disease inthe manufacture of a medicament for the treatment of a disease mediatedby inhibition of RIP2 kinase

In a further aspect there is provided a method of treating allergicdisease, inflammation or autoimmune disease comprising administering toa human in need thereof a therapeutically effective amount of acombination comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and at least one further therapeutic agentuseful in the treatment of a disease mediated by inhibition of RIP2kinase.

In a further aspect there is provided a pharmaceutical compositioncomprising a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and at least one furthertherapeutic agent useful in the treatment of a disease mediated byinhibition of RIP2 kinase and one or more of pharmaceutically acceptableexcipients.

General Synthetic Methods

Compounds of general formula (I) may be prepared by methods known in theart of organic synthesis. In all of the methods, it is well understoodthat protecting groups for sensitive or reactive groups may be employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1999) ProtectiveGroups in Organic Synthesis, 3^(rd) edition, John Wiley & Sons). Thesegroups are removed at a convenient stage of the compound synthesis usingmethods that are readily apparent to those skilled in the art. Theselection of processes as well as the reaction conditions and order oftheir execution shall be consistent with the preparation of compounds ofFormula (I).

In particular, methods for preparing IAP compounds included in thepresent invention can be found in WO 2014/047024, WO 2014/055461, WO2014/031487 and WO 2008/128171

Methods for preparing RIP2 inhibitors included in the present inventioncan be found in WO 2014/128622, WO 2014/043437, WO 2013/025958, WO2012/122011, WO 2012/021580 and WO 2011/140442.

Experimental Abbreviations

DCM: dichloromethane.

DIPEA: N,N-diisopropylethylamine. DMF: N,N-dimethylformamide.

hr: hour.HATU: 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate.HPLC: high-performance liquid chromatography.LCMS: liquid chromatography-mass spectrometryMin: minutes.

NM P: N-methylpyrrolidone.

NMR: Nuclear magnetic resonance.RT retention time.tBu: tert-butoxide.TFA: trifluoroacetic acid.THF: tetrahydrofuran.

LCMS Method A:

Unless specified, Method A was used for analysis.

The analysis was conducted on an Acquity UPLC BEH C18 column (50 mm×2.1mm internal diameter 1.7 μm packing diameter) at 40° C.

The solvents employed were:

A=0.1% v/v solution of formic acid in water.

B=0.1% v/v solution of formic acid in acetonitrile.

The gradient employed was as follows:

Time Flow Rate (minutes) (mL/min) % A % B 0 1 97 3 1.5 1 0 100 1.9 1 0100 2.0 1 97 3

The UV detection was an averaged signal from wavelength of 210 nm to 350nm and mass spectra were recorded on a mass spectrometer usingalternate-scan positive and negative mode electrospray ionization.

LCMS Method B:

The analysis was conducted on an Acquity UPLC BEH C18 column (50 mm×2.1mm internal diameter 1.7 μm packing diameter) at 40° C.

The solvents employed were:

A=10 mM ammonium bicarbonate in water adjusted to pH 10 with ammoniasolution.

B=acetonitrile.

The gradient employed was as follows:

Time Flow Rate (minutes) (mL/min) % A % B 0 1 99 1 1.5 1 3 97 1.9 1 3 972.0 1 99 1

The UV detection was an averaged signal from wavelength of 210 nm to 350nm and mass spectra were recorded on a mass spectrometer usingalternate-scan positive and negative mode electrospray ionization.

LCMS Method C:

The analysis was conducted on an Acquity UPLC CSH C18 column (50 mm×2.1mm internal diameter 1.7 μm packing diameter) at 40° C.

The solvents employed were:

A=0.1% v/v solution of trifluoroacetic acid in water.

B=0.1% v/v solution of trifluoroacetic acid in acetonitrile.

The gradient employed was as follows:

Time Flow Rate (minutes) (mL/min) % A % B 0 1 95 5 1.5 1 5 95 1.9 1 5 952.0 1 95 5

The UV detection was an averaged signal from wavelength of 210 nm to 350nm and mass spectra were recorded on a mass spectrometer usingalternate-scan positive and negative mode electrospray ionization.

The following illustrates the mobile phases and gradients used whencompounds underwent purification by mass-directed autopreparative HPLC.

Mass-Directed Autopreparative HPLC (Formic Acid Modifier)

The HPLC analysis was conducted on a Sunfire C18 column (150 mm×30 mminternal diameter, 5 μm packing diameter) at ambient temperature.

The solvents employed were:

A=0.1% v/v solution of formic acid in water.

B=0.1% v/v solution of formic acid in acetonitrile.

Mass-Directed Autopreparative HPLC (Trifluoroacetic Acid Modifier)

The HPLC analysis was conducted on a Sunfire C18 column (150 mm×30 mminternal diameter, 5 μm packing diameter) at ambient temperature.

The solvents employed were:

A=0.1% v/v solution of trifluoroacetic acid in water.

B=0.1% v/v solution of trifluoroacetic acid in acetonitrile.

Mass-Directed Autopreparative HPLC (Ammonium Bicarbonate Modifier)

The HPLC analysis was conducted on an XBridge C18 column (150 mm×30 mminternal diameter, 5 μm packing diameter) at ambient temperature.

The solvents employed were:

A=10 mM ammonium bicarbonate in water adjusted to pH 10 with ammoniasolution.

B=acetonitrile.

For each of the mass-directed autopreparative purifications,irrespective of the modifier used, the gradient employed was dependentupon the retention time of the particular compound undergoingpurification as recorded in the analytical LCMS, and was as follows:

For compounds with an analytical LCMS retention time below 0.6 minutesthe following gradient was used:

Time Flow Rate (minutes) (mL/min) % A % B 0 40 99 1 1 40 99 1 10 40 7030 11 40 1 99 15 40 1 99

For compounds with an analytical LCMS retention time between 0.6 and 0.9minutes the following gradient was used:

Time Flow Rate (minutes) (mL/min) % A % B 0 40 85 15 1 40 85 15 10 40 4555 11 40 1 99 15 40 1 99

For compounds with an analytical LCMS retention time between 0.9 and 1.2minutes the following gradient was used:

Time Flow Rate (minutes) (mL/min) % A % B 0 40 70 30 1 40 70 30 10 40 1585 11 40 1 99 15 40 1 99

For compounds with an analytical LCMS retention time between 1.2 and 1.4minutes the following gradient was used:

Time Flow Rate (minutes) (mL/min) % A % B 0 40 50 50 1 40 50 50 10 40 199 11 40 1 99 15 40 1 99

For compounds with an analytical LCMS retention time greater than 1.4minutes (LCMS method A) or greater than 3.6 minutes (LCMS method B) thefollowing gradient was used:

Time Flow Rate (minutes) (mL/min) % A % B 0 40 20 80 1 40 20 80 10 40 199 11 40 1 99 15 40 1 99

The UV detection was an averaged signal from wavelength of 210 nm to 350nm and mass spectra were recorded on a mass spectrometer usingalternate-scan positive and negative mode electrospray ionization.

The chemical names were generated using ChemBioDraw Ultra v12 fromCambridgeSoft.

(S)-Tert-butyl7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of(S)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid (commercially available from, for example, Fluorochem) (1 g, 3.41mmol) and (R)-1,2,3,4-tetrahydronaphthalen-1-amine (commerciallyavailable from, for example, Aldrich) (0.552 g, 3.8 mmol) in DMF (4 mL)was treated with DIPEA (1.8 mL, 10.2 mmol) and then with HATU (1.56 g,4.1 mmol) and stirred at ambient temperature for 30 minutes. The mixturewas treated with dichloromethane (60 mL), saturated aqueous sodiumbicarbonate (10 mL) and water (10 mL) and separated through ahydrophobic frit. The organic phase was evaporated to dryness and theproduct was purified by chromatography on silica using a gradientelution from 0% to 100% ethyl acetate in cyclohexane to afford the titlecompound (1.18 g, 2.8 mmol, 82% yield). LCMS RT=1.10 min, ES+ve 423.

(S)-7-Hydroxy-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,Hydrochloride

A solution of (S)-tert-butyl7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.18 g, 2.8 mmol) in tetrahydrofuran (10 mL) was treated withhydrochloric acid (4M in 1,4-dioxan) (10 mL, 40 mmol) and the mixturewas stood at ambient temperature overnight. The mixture was removed ofsolvent in vacuo to afford the title compound (943 mg, 2.6 mmol, 94%yield). LCMS RT=0.58 min, ES+ve 323.

Tert-butyl((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

A mixture of(S)-7-hydroxy-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,hydrochloride (933 mg, 2.6 mmol) and(S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (631 mg,2.7 mmol) in DMF (10 mL) was treated with DIPEA (1.82 mL, 10.4 mmol) andthen with HATU (1.19 g, 3.12 mmol) and stirred at ambient temperaturefor 1 hour. The mixture was treated with dichloromethane (80 mL),saturated aqueous sodium bicarbonate (10 mL) and water (10 mL) andseparated through a hydrophobic frit. The organic phase was evaporatedto dryness and the product was purified by chromatography on silicausing a gradient elution from 0% to 100% ethyl acetate in cyclohexane toafford the title compound (923 mg, 1.72 mmol, 66% yield). LCMS RT=1.27min, ES+ve 536.

(S)-2-((S)-2-Amino-3,3-dimethylbutanoyl)-7-hydroxy-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,Hydrochloride

A solution of tert-butyl((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(915 mg, 1.71 mmol) in tetrahydrofuran (4 mL) was treated withhydrochloric acid (4M in 1,4-dioxan) (5 mL, 20 mmol) and then stirred atambient temperature overnight. The mixture was evaporated to dryness toafford the title compound (780 mg, 1.65 mmol, 97% yield). LCMS RT=0.69min, ES+ve 436.

Tert-butyl((S)-1-(((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A mixture of(S)-2-((S)-2-amino-3,3-dimethylbutanoyl)-7-hydroxy-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,hydrochloride (770 mg, 1.63 mmol) and(S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (332 mg, 1.63mmol) in DMF (4 mL) was treated with DIPEA (1.14 mL, 6.5 mmol) and thenwith HATU (744 mg, 2.0 mmol) and stirred at ambient temperatureovernight. The product was purified by chromatography on silica using agradient elution from 0% to 100% ethyl acetate in cyclohexane to affordthe title compound (780 mg, 1.26 mmol, 77% yield). LCMS RT=1.29 min,ES+ve 621.

Tert-butyl((S)-1-(((S)-1-((S)-7-(2-(2-(2-(2-chloroethoxy)ethoxy)ethoxy)ethoxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A solution of tert-butyl((S)-1-(((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(200 mg, 0.32 mmol) in DMF (4 mL) was treated with1-chloro-2-(2-(2-(2-chloroethoxy)ethoxy)ethoxy)ethane (commerciallyavailable from, for example, Aldrich) (298 mg, 1.3 mmol) and potassiumcarbonate (134 mg, 1.0 mmol) and heated at 80° C. overnight. The productwas subjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound(165 mg, 0.20 mmol, 63% yield). LCMS RT=1.44 min, ES+ve 816.

5-(((4-Bromo-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

2,2-Dimethyl-1,3-dioxane-4,6-dione (8.5 g, 58 mmol) in trimethylorthoformate (50 mL, 450 mmol) was refluxed at 105° C. for 1 hr.4-Bromo-3-methoxyaniline (commercially available from, for example,Aldrich) (10.5 g, 50 mmol) was then added and refluxing was continuedfor an additional hour. The suspension was filtered, and the solid waswashed with methanol and vacuum dried to yield the title compound (17.0g, 49 mmol, 96% yield). LCMS RT=1.10 min, ES+ve 356,358

6-Bromo-7-methoxyquinolin-4-ol

To diphenyl ether (68 mL, 420 mmol) at 230° C. was added5-({[4-bromo-3-(methyloxy)phenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione(15 g, 42 mmol), and the mixture was stirred for 1 hr. The reactionmixture was poured into hexane after being cooled to room temperature.The precipitate was filtered and washed with hexane. The brown solid wasdried under vacuum overnight to afford the title compound (10.0 g, 33mmol, 79% yield). LCMS RT=0.63 min, ES+ve 254,256

6-Bromo-4-chloro-7-methoxyquinoline

6-Bromo-7-(methyloxy)-4-quinolinol (4.17 g, 16.4 mmol) in phosphorusoxychloride (8 mL, 82 mmol) was stirred at 110° C. for 1 hr. Thereaction mixture was cooled and cautiously poured into saturated aqueoussodium carbonate with ice while stirring. The resulting suspension wasfiltered, the solid was washed with water and vacuum-dried overnight toyield the title compound (4.6 g, 16 mmol, 97% yield). LCMS RT=1.18 min,ES+ve 272,274

6-(Tert-butylthio)-4-chloro-7-methoxyquinoline

A mixture of 6-bromo-4-chloro-7-methoxyquinoline (50 g, 183 mmol),Pd(PPh₃)₄ (5.30 g, 4.59 mmol), sodium carbonate (48.6 g, 459 mmol) and1,4-dioxane (895 mL) was purged with nitrogen for 10 minutes.2-Methyl-2-propanethiol (22.8 mL, 202 mmol) was added and the reactionwas heated at 70° C. for 4 d. The reaction was cooled to rt and flushedthrough a silica gel plug that had been pre-wetted with EtOAc using 100%EtOAc as the eluent. The product-containing fractions were combined andtriturated with MeOH to afford the title compound (37.5 g, 128 mmol, 70%yield). LCMS RT=1.31 min, ES+ve 282

6-(Tert-butylsulfonyl)-4-chloro-7-methoxyquinoline

(Tert-butylthio)-4-chloro-7-methoxyquinoline (18.5 g, 63 mmol) in ethylacetate (315 mL) and water (315 mL) was treated with Oxone® (44.6 g,72.5 mmol) and stirred at rt for 18 hours. The mixture was separated andthe aqueous phase was extracted twice with ethyl acetate. The combinedorganic extracts were concentrated to dryness. The residue was dissolvedin a minimal amount of 10% methanol/dichloromethane, loaded onto a 340 gpre-packed silica cartridge and purified via column chromatography (100%ethyl acetate, then 0-20% methanol in ethyl acetate). Product-containingfractions were evaporated to dryness and triturated with EtOAc to yieldthe title compound (15.2 g, 48 mmol, 77% yield). LCMS RT=0.97 min, ES+ve314

N-(6-(Tert-butylsulfonyl)-7-methoxyquinolin-4-yl)benzo[d]thiazol-5-amine

A mixture of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline (2 g,6.4 mmol) and benzo[d]thiazol-5-amine (0.957 g, 6.4 mmol) in ethanol (10mL) was irradiated by microwave at 150° C. for 15 mins. The cooledreaction mixture was partitioned between ethyl acetate and saturatedsodium bicarbonate. The aqueous layer was extracted with EtOAc twice andthe combined EtOAc layers were dried over magnesium sulfate, filteredand evaporated to dryness. The residue was purified via flashchromatography (100 g pre-packed silica cartridge) using a gradientelution from 0-75% ethyl acetate/cyclohexane to yield the title compound(2.11 g, 4.9 mmol, 77% yield). LCMS RT=0.58 min, ES+ve 428

4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-ol

To a solution ofN-(6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)benzo[d]thiazol-5-aminehydrochloride (5.35 g, 11.5 mmol) in DMF (50 mL) was added sodiumpropane-2-thiolate (5.66 g, 58 mmol). The reaction was then heated to150° C. for 1 hour. It was cooled to rt and concentrated under vacuum.The residue was treated with ethanol (70 mL) and stirred at 60° C. for15 minutes, cooled in ice then the yellow precipitated product wasfiltered off, washed with minimum ethanol and dried under vacuum toafford the title compound (4.55 g, 11 mmol, 95% yield). LCMS RT=0.57min, ES+ve 414

Tert-butyl14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-oate

A solution of tert-butyl14-(tosyloxy)-3,6,9,12-tetraoxatetradecan-1-oate (1.35 g, 2.9 mmol) inDMF (2.5 mL) was added to a stirred solution of4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-ol (802mg, 1.94 mmol) and caesium carbonate (948 mg, 2.91 mmol) in DMF (2.5mL). The reaction mixture was stirred at 50° C. for 16 hours. Thereaction mixture was then partitioned between EtOAc (150 mL) and water(150 mL). The organic layer was separated, washed with water (50 mL),brine (50 mL), dried using a hydrophobic frit and concentrated underreduced pressure. The sample was purified using a C18-silica column (120g) using a gradient elution from 5-95% acetonitrile in water with 0.1%formic acid to afford the title compound. LCMS RT=0.80 min, ES+ve 704.

14-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-oicacid

Trifluoroacetic acid (0.49 mL, 6.4 mmol) was added to a solution oftert-butyl14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-oate(90 mg, 0.13 mmol) in THF (1 mL) and stirred for 6 hours. The reactionmixture was diluted with DCM (20 mL) and concentrated under reducedpressure three times and then repeated using toluene as the solvent toafford the title compound (78 mg, 0.12 mmol, 94% yield). LCMS RT=0.62min, ES+ve 648.

(2S,4S)-1-Tert-butyl 2-methyl4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)pyrrolidine-1,2-dicarboxylate

HATU (678 mg, 1.78 mmol) was added to a mixture of14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-oicacid (1.05 g, 1.62 mmol), (2S,4S)-1-tert-butyl 2-methyl4-aminopyrrolidine-1,2-dicarboxylate, hydrochloride (592 mg, 2.1 mmol),DIPEA (0.85 mL, 4.9 mmol), and DMF (10 mL). The reaction was stirred atambient temperature for 30 min. The reaction mixture was then dilutedwith water (50 mL) and extracted using ethyl acetate (2×50 mL). Theorganic solution was then washed once with 50% brine solution (50 mL)and once with brine (50 mL). The solution was then concentrated underreduced pressure and purified using a 120 g C-18/silica column using agradient of 10-95% acetonitrile in water with 0.1% formic acid modifierto afford the title compound (759 mg, 0.87 mmol, 54% yield). LCMSRT=0.79 min, ES+ve 874.

(2S,4S)-Methyl4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)pyrrolidine-2-carboxylate,Hydrochloride

Hydrochloric acid (4M in dioxane) (0.65 mL, 2.6 mmol) was added to(2S,4S)-1-tert-butyl 2-methyl4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)pyrrolidine-1,2-dicarboxylate(76 mg, 0.087 mmol) in DCM (0.5 mL), and the mixture was stirred at roomtemperature for 45 min. The solvent was removed under reduced pressure,and the residue was re-evaporated with DCM (3×20 mL) followed by toluene(20 mL) to afford the title product (72 mg, 0.089 mmol, 100% yield).LCMS RT=0.49 min, ES+ve 774.

(2S,4S)-methyl4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-v)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylate

HATU (351 mg, 0.92 mmol) was added to a mixture of (2S,4S)-methyl4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)pyrrolidine-2-carboxylate(650 mg, 0.84 mmol),(S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoicacid (345 mg, 1.1 mmol), DIPEA (0.44 mL, 2.5 mmol), and DMF (10 mL). Thereaction mixture was stirred at ambient temperature for 3 hr. Themixture was diluted with water (50 mL) and the product extracted usingethyl acetate (2×50 mL). This organic fraction was washed first with 50%brine solution (75 mL) and then with brine (75 mL). The solution waspassed through a hydrophobic frit and concentrated under reducedpressure. The sample was purified using a 120 g C18-Silica column usinga gradient elution from 10-95% acetonitrile in water and 0.1% formicacid modifier to afford the title compound (517 mg, 0.48 mmol, 57%yield). LCMS RT=0.89 min, ES+ve 537.

(2S,4S)-4-(14-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylicacid

To a solution of (2S,4S)-methyl4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylate(517 mg, 0.48 mmol) in THF (2.5 mL) was added 2M aqueous sodiumhydroxide (2.4 mL, 4.8 mmol). The reaction mixture was stirred atambient temperature for 1.5 h. The pH of the solution was adjusted toabout 2 using 0.1 M hydrochloric acid solution. The mixture was thenpartitioned between ethyl acetate (50 mL) and water (50 mL). The aqueouslayer was washed once with a further portion of ethyl acetate (50 mL),the two organic fractions were then combined and washed first with 50%brine solution (75 mL) and then with brine (75 mL). The organic solutionwas passed through a hydrophobic frit and concentrated under reducedpressure to afford the title compound (503 mg, 0.48 mmol, 99% yield).LCMS RT=0.93 min, ES+ve 1059.

Tert-butyl((S)-1-(((S)-1-((2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-2-(((R)-3-methylbutan-2-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

HATU (17.4 mg, 0.046 mmol) was added to a mixture of(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylicacid (44 mg, 0.042 mmol), (R)-3-methylbutan-2-amine (6.3 μl, 0.054mmol), DIPEA (0.022 mL, 0.13 mmol), in DMF (1 mL). The reaction mixturewas stirred at ambient temperature for 18 hr then directly loaded onto a30 g C18-Silica column and purified using a gradient from 10-95%acetonitrile in water with a 0.1% formic acid modifier to afford thetitle compound (20.4 mg, 0.018 mmol, 44% yield). LCMS RT=1.33 min, ES+ve1127.

The following compounds were prepared by a method analogous to that fortert-butyl((S)-1-(((S)-1-((2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-2-(((R)-3-methylbutan-2-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate:

LCMS Compound Name/Structure Yield RT ES + ve Tert-butyl((S)-1-(((S)-1-((2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)- 49%Method  594 6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12- B (M +tetraoxatetradecanamido)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1- 1.382H)2+yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-mins oxopropan-2-yl)(methyl)carbamate

Tert-butyl((S)-1-(((S)-1-((2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)- 36%Method 1173 6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12- Btetraoxatetradecanamido)-2-(((R)-2,3-dihydro-1H-inden-1- 1.33yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-mins oxopropan-2-yl)(methyl)carbamate

Tert-butyl((S)-1-(((S)-1-((2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)- 40%Method 1175 6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12- Btetraoxatetradecanamido)-2-(((R)-1-phenylpropyl)carbamoyl)pyrrolidin-1-1.34 yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2- minsyl)(methyl)carbamate

Tert-butyl((S)-1-(((S)-1-((2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)ox)-3,6,9,12-tetraoxatetradecanamido)-2-((2,6-difluorophenyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylicacid (50 mg, 0.047 mmol) and 2,6-difluoroaniline (6.1 μl, 0.057 mmol) inpyridine (5 mL) at 0° C. was added phosphoryl trichloride (7 μl, 0.071mmol). The reaction was warmed to rt and stirred for 2 h. The mixturewas evaporated to dryness, water (30 mL) was added and the resultingmixture was extracted with EtOAc (2×30 mL). The combined organic layerwas washed with water (50 mL), brine (50 mL), passed through ahydrophobic frit and concentrated under vacuum. The crude material waspurified using mass directed auto-preparative HPLC to afford the titlecompound (27 mg, 0.023 mmol, 49% yield). LCMS RT=1.26 min, ES+ve 1169.

6-(Tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine

A mixture of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline (200 mg,0.64 mmol) and 5-fluoro-1H-indazol-3-amine (106 mg, 0.70 mmol) was takenup in ethanol (3 mL) and 3 drops of conc HCl were added. The reactionmixture was stirred at rt overnight, then concentrated and the residuewas purified by flash chromatography (gradient elution from 0-10% MeOH(with 1% NH₄OH) in DCM). Concentration of the desired fractions affordedthe title compound (240 mg, 0.56 mmol, 88% yield). LCMS RT=0.60 min,ES+ve 429.

6-(Tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-ol

To a solution of6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)-7-methoxyquinolin-4-amine(2 g, 4.7 mmol) in DMF (30 mL) was added sodium2-methylpropane-2-thiolate (2.62 g, 23.3 mmol). The reaction was thenheated to 150° C. for 1 hour. It was then cooled to rt and concentratedunder vacuum. The residue was purified by flash chromatography (0->15%MeOH with 1% NH₄OH in DCM). Desired fractions were combined andconcentrated to afford6-(tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-ol(1.22 g, 2.9 mmol, 63% yield). LCMS RT=0.61 min, ES+ve 415.

6-(Tert-butylsulfonyl)-7-(2-(2-(2-(2-chloroethoxy)ethoxy)ethoxy)ethoxy)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine

To a solution of6-(tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-ol(100 mg, 0.24 mmol) in N-methyl-2-pyrrolidone (NMP) (1.0 mL) was added1-chloro-2-(2-(2-(2-chloroethoxy)ethoxy)ethoxy)ethane (167 mg, 0.72mmol), sodium iodide (3.6 mg, 0.024 mmol) and potassium carbonate (100mg, 0.72 mmol) and the reaction mixture was sealed and stirred at 95° C.in a Biotage microwave for 1 hour. The product was purified by flashchromatography (30 g pre-packed C-18 SNAP cartridge using a gradientfrom 30%-85% acetonitrile (with 0.1% ammonia) in water (10 mM ammoniumbicarbonate)). Desired fractions were combined and concentrated toafford the title compound (90 mg, 0.15 mmol, 62% yield). LCMS Method BRT=1.08 min, ES+ve 609.

(S)-Methyl2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoate

A mixture of (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid(2.8 g, 13.8 mmol) and (S)-methyl 2-amino-3,3-dimethylbutanoate,hydrochloride (2.52 g, 13.9 mmol) in THF (160 mL) was treated with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.28 g, 27.6 mmol) andHOBt (2.38 g, 15.6 mmol). The mixture was stirred at ambient temperaturefor 18 hours and then treated with water (50 mL) and ethyl acetate (75mL). The organic phase was washed with 1M HCl (70 mL×2), saturatedsodium bicarbonate (100 mL) and brine (50 mL), dried over magnesiumsulfate, filtered and evaporated to dryness to afford the title compound(4.11 g, 12.4 mmol, 90% yield). LCMS RT=1.13 min, ES+ve 331.

(S)-2-((S)-2-((Tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoicacid

A solution of (S)-methyl2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoate(4.11 g, 12.4 mmol) in a mixture of THF (40 mL), methanol (20 mL) andwater (40 mL) was treated with a solution of lithium hydroxide (1.19 g,50 mmol) in water (30 mL) and then stirred at ambient temperature for 18hours. The mixture was treated with 1M HCl (150 mL) and extracted withethyl acetate (3×50 mL), washed with brine (80 mL), dried over magnesiumsulfate and evaporated to dryness to afford the title compound (3.32 g,10.5 mmol, 84% yield). LCMS RT=0.98 min, ES+ve 317.

(2S,4S)-1-Tert-butyl 2-methyl4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidine-1,2-dicarboxylate

(2S,4S)-1-Tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate(0.8 g, 3.26 mmol) was dissolved in anhydrous THF (20 mL) undernitrogen. The solution was cooled to −10° C. before sodium hydride (60%w/w in mineral oil) (0.196 g, 4.9 mmol) was added and the reactionmixture left to stir for 15 minutes. A solution of1-phenyl-2,5,8,11-tetraoxatridecan-13-yl 4-methylbenzenesulfonate (1.29g, 2.9 mmol) in THF (5 mL) was then added to the reaction mixturedropwise over a period of five minutes. The reaction mixture was allowedto warm to 0° C. and stirred for 4 hours, then stirred at rt for afurther 48 hours. The solution was re-cooled to 0° C. and cautiouslyquenched using saturated aqueous ammonium chloride (50 mL). The productwas then extracted using ethyl acetate (2×50 mL) and washed with brine(80 mL), dried (MgSO₄), filtered and evaporated to dryness. The productwas purified by chromatography on silica using a gradient elution from0%-100% ethyl acetate in cyclohexane to afford the title compound (1.41g, 2.8 mmol, 84% yield). LCMS RT=1.17 min, ES+ve 512.

(2S,4S)-Methyl4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidine-2-carboxylate,hydrochloride

A solution of (2S,4S)-1-tert-butyl 2-methyl4-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)pyrrolidine-1,2-dicarboxylate(580 mg, 1.24 mmol) in methanol (1 mL) was treated with hydrochloricacid (4M in dioxane) (4 mL, 16 mmol) and the mixture was stirred atambient temperature for 1 hour. The mixture was evaporated to dryness toafford the title compound (1.22 g, 2.7 mmol, 99% yield). LCMS RT=0.59min, ES+ve 412.

(2S,4S)-Methyl1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yloxy)pyrrolidine-2-carboxylate

A mixture of (2S,4S)-methyl4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidine-2-carboxylate,hydrochloride (1.3 g, 2.9 mmol) and(S)-2-((S)-2-((tertbutoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoicacid (1.102 g, 3.5 mmol) in DMF (10 mL) was treated with DIPEA (2 mL,11.6 mmol), then with HATU (1.324 g, 3.5 mmol) and then stirred atambient temperature for 24 hours. The mixture was treated withdichloromethane (40 mL) and saturated aqueous sodium bicarbonate (20 mL)and separated. The organic phase was evaporated to dryness and theproduct was purified by chromatography on silica using a gradientelution from 0%-50% ethyl acetate in dichloromethane to afford the titlecompound (1.34 g, 1.9 mmol, 65% yield). LCMS RT=1.28 min, ES+ve 710.

(2S,4S)-1-((S)-2-((S)-2-((Tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidine-2-carboxylicacid

A solution of (2S,4S)-methyl1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidine-2-carboxylate(400 mg, 0.56 mmol) in THF (10 mL), methanol (5 mL) and water (15 mL)was treated with lithium hydroxide (27 mg, 1.13 mmol) and stirred at rtfor 4 hours. The mixture was treated with ethyl acetate (50 mL) and 1Maqueous HCl (20 mL). The organic phase was washed with brine (20 mL),dried (MgSO₄), filtered and evaporated to dryness to afford the titlecompound (288 mg, 0.41 mmol, 74% yield). LCMS RT=1.18 min, ES+ve 696.

Tert-butyl((S)-1-(((S)-3,3-dimethyl-1-oxo-1-((2S,4S)-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)butan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A mixture of(2S,4S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidine-2-carboxylicacid (370 mg, 0.53 mmol) and (R)-1,2,3,4-tetrahydronaphthalen-1-amine(86 mg, 0.59 mmol) in DMF (5 mL) was treated with DIPEA (0.37 mL, 2.13mmol), then with HATU (243 mg, 0.64 mmol) and then stirred at ambienttemperature for 1 hour. The mixture was partitioned betweendichloromethane (10 mL) and saturated aqueous sodium bicarbonate (10mL). The organic phase was evaporated to dryness and the product waspurified by chromatography on silica using a gradient elution from 0%-5%methanol in ethyl acetate to afford the title compound (375 mg, 0.46mmol, 85% yield). LCMS RT=1.43 min, ES+ve 825.

Tert-butyl((S)-1-(((S)-1-((2S,4S)-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A solution of tert-butyl((S)-1-(((S)-3,3-dimethyl-1-oxo-1-((2S,4S)-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)butan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(410 mg, 0.50 mmol) in ethanol (10 mL) was added in an inert atmosphereto 10% palladium on carbon (degussa type, 100 mg) and then stirred in anatmosphere of hydrogen for 2 hours. The mixture was filtered throughcelite and evaporated to dryness to afford the title compound (314 mg,0.43 mmol, 86% yield). LCMS RT=1.17 min, ES+ve 735.

2-(2-(2-(2-(((3S,5S)-1-((S)-2-((S)-2-((Tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethylmethanesulfonate

An ice-cooled solution of tert-butyl((S)-1-(((S)-1-((2S,4S)-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(300 mg, 0.41 mmol) in dichloromethane (10 mL) was treated with DIPEA(0.107 mL, 0.61 mmol) and then with methanesulfonyl chloride (0.038 mL,0.49 mmol) and the mixture was stirred for 30 minutes at 0° C. and at rtfor a further 30 minutes. The mixture was then treated withdichloromethane (10 mL) and saturated aqueous sodium bicarbonate (20 mL)and separated. The organic fraction was evaporated to dryness to affordthe title compound (315 mg, 0.39 mmol, 95% yield). LCMS RT=1.25 min,ES+ve 813.

Tert-butyl((S)-1-(((S)-1-((2S,4S)-4-(2-(2-(2-(2-((6-(tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A mixture of6-(tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-ol(61.3 mg, 0.148 mmol), potassium carbonate (51 mg, 0.37 mmol) and sodiumiodide (18.4 mg, 0.12 mmol) was treated with a solution of2-(2-(2-(2-(((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethylmethanesulfonate (100 mg, 0.12 mmol) in DMF (2 mL) and the mixture washeated at 80° C. for 4 hours. The cooled mixture was filtered andsubjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound (46mg, 0.04 mmol, 33% yield). LCMS RT=1.04 min, ES+ve 516 ([M+2H]²⁺).

Tert-butyl14-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-oate

To a solution of6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-ol(140 mg, 0.37 mmol, obtained as described in WO 2014/128622) in DMF (2mL) was added tert-butyl14-(tosyloxy)-3,6,9,12-tetraoxatetradecan-1-oate (259 mg, 0.56 mmol,prepared as described in Nature Chemical Biology, 2015, 11, p611),potassium carbonate (155 mg, 1.1 mmol) and sodium iodide (56 mg, 0.37mmol) and reaction stirred at 80° C. for 2 hours. The product wassubjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound (35mg, 0.046 mmol, 12% yield). LCMS RT=0.83 min, ES+ve 666.

2-((6-(Tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethanol

To a solution of6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-fluoroquinazolin-4-amine(250 mg, 0.66 mmol, obtained as described in WO 2014/128622) in ethyleneglycol (923 μl, 16.6 mmol) was added sodium hydride (79 mg, 3.3 mmol)and the reaction mixture was sealed stirred at 100° C. for 105 minutesin a Biotage microwave. The mixture was cooled to room temperature andsubjected directly to purification by flash chromatography (60 gpre-packed C-18 SNAP cartridge: 5% to 30% acetonitrile (0.1% formicacid) in water (0.1% formic acid)). Desired fractions were combined andconcentrated to afford the title compound (200 mg, 0.48 mmol, 72%yield). LCMS RT=0.54 min, ES+ve 420.

6-(Tert-butylsulfonyl)-7-(2-((2-chloropyrimidin-5-yl)oxy)ethoxy)-N-(3,4-dimethyl-1H-pyrazol-5-yl)quinazolin-4-amine

To a solution of2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethanol(247 mg, 0.59 mmol) in THF (5 mL) was added 2-chloropyrimidin-5-ol (85mg, 0.65 mmol), triphenylphosphine (232 mg, 0.88 mmol) and DIAD (0.172mL, 0.88 mmol) and the reaction mixture was stirred at rt under anatmosphere of nitrogen for 42 hours. The reaction mixture wasconcentrated, and the residue subjected directly to purification byflash chromatography (60 g pre-packed C-18 SNAP cartridge: 5% to 30%acetonitrile (0.1% formic acid) in water (0.1% formic acid)). Desiredfractions were combined and concentrated to afford the title compound(167 mg, 0.31 mmol, 53% yield). LCMS RT=0.73 min, ES+ve 532.

6-(Tert-butylsulfonyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)-7-(piperidin-4-yloxy)quinazolin-4-amine

Under nitrogen, a mixture of6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-fluoroquinazolin-4-amine(300 mg, 0.795 mmol, obtained as described in WO 2014/128622) andpiperidin-4-ol (402 mg, 4.0 mmol) in dioxane (5 mL) and NMP (1.5 mL) wastreated with sodium hydride (60% in mineral oil, 57 mg, 2.4 mmol) andstirred for 10 minutes. The mixture was then heated at 80° C. for 4hours and cooled, treated with acetic acid (0.5 mL) and concentrated toabout 1.5 mL. The product was subjected to purification by mass-directedautomated preparative HPLC (ammonium bicarbonate modifier) to afford thetitle compound (270 mg, 0.59 mmol, 74% yield). LCMS RT=0.46 min, ES+ve459.

6-(Tert-butylsulfonyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)-7-(piperidin-4-ylmethoxy)quinazolin-4-amine

Under nitrogen, a mixture of6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-fluoroquinazolin-4-amine(300 mg, 0.795 mmol, obtained as described in WO 2014/128622) andpiperidin-4-ylmethanol (275 mg, 2.39 mmol) in 1,4-dioxane (5 mL) and NMP(1.5 mL) was treated with sodium hydride (191 mg, 4.8 mmol) and stirredfor 10 minutes. The mixture was then heated at 80° C. for 4 hours andcooled. The mixture was treated with acetic acid (0.5 mL) and evaporateddown to about 1.5 mL. The product was subjected to purification bymass-directed automated preparative HPLC (ammonium bicarbonate modifier)to afford the title compound (298 mg, 0.63 mmol, 79% yield). LCMSRT=0.44 min, ES+ve 473.

Tert-butyl4-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylate

An ice-cooled suspension of sodium hydride (60% w/w in mineral oil, 1.59g, 40 mmol) in 1,4-dioxane (15 mL) was treated dropwise with a solutionof tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (9.15 g, 40mmol) in 1,4-dioxane (20 mL). The mixture was stirred for 20 mins andthen treated with6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-fluoroquinazolin-4-amine(3 g, 8.0 mmol). The reaction mixture was stirred for 30 mins and thenheated to 100° C. and stirred vigorously for a further hour. The mixturewas then cooled and acidified to pH 7 with aqueous HCl (2M) and thenpartitioned between water and ethyl acetate. The aqueous layer wasextracted with ethyl acetate (2×40 mL). The combined organic layer waswashed with water (40 mL), brine (40 mL) and then dried over magnesiumsulfate, filtered, concentrated in vacuo, and the residue subjecteddirectly to purification by flash chromatography (100 g pre-packedsilica cartridge: 0-50% methanol in tert-butyl methyl ether). Desiredfractions were combined and concentrated to afford the title compound(1.31 g, 2.2 mmol, 27% yield). LCMS Method B RT=1.04 min, ES+ve 588.

6-(Tert-butylsulfonyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-amine

To a solution of tert-butyl4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylate(1.3 g, 2.2 mmol) in THF (5 mL) and methanol (10 mL) under nitrogen wasadded HCl (4M in dioxan) (5 mL, 20 mmol). The mixture was stirred atroom temperature for 6 hours then filtered under vacuum to afford thetitle compound (1.25 g, 2.10 mmol, 95% yield). LCMS Method B RT=0.74min, ES+ve 488.

Methyl6-(4-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)nicotinate

To a solution of6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-amine,3Hydrochloride (400 mg, 0.67 mmol) in NMP (2 mL) was added DIPEA (0.585mL, 3.4 mmol) and methyl 6-chloronicotinate (138 mg, 0.80 mmol), thensealed and heated at 120° C. by in a Biotage microwave for 3 hours. Theproduct was directly purified by flash chromatography (60 g pre-packedC-18 SNAP cartridge: 30-85% acetonitrile (0.1% ammonia) in water (10 mMammonium formate)). Desired fractions were combined and concentrated toafford the title compound (261 mg, 0.42 mmol, 63% yield). LCMS Method BRT=1.00 min, ES+ve 623.

6-(4-(2-((6-(Tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)nicotinicacid

To a solution of methyl6-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)nicotinate(261 mg, 0.42 mmol) in methanol (2 mL) was added lithium hydroxide (1Msolution in water, 2.24 mL) and the reaction mixture was stirred at 40°C. for 25 hours. The mixture was neutralised with HCl (4M in dioxane, 1mL, 4 mmol) and evaporated to dryness to afford the title compound,which was used without further purification (291 mg, 0.41 mmol, 97%yield). LCMS RT=0.52 min, ES+ve 609.

The following compounds were prepared by a method sequence analogous tothat for6-(4-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)nicotinicacid:

Compound Name/Structure Yield LCMS RT ES + ve Tert-butyl4-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H- 52% Method B 587pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethyl)piperidine-1- 1.17 minscarboxylate

6-(Tert-butylsulfonyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)-7-(2- 85% MethodB 487 (piperidin-4-yl)ethoxy)quinazolin-4-amine 0.95 mins

Methyl 6-(4-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H- 35% MethodB 622 pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-1- 1.14mins yl)nicotinate

6-(4-(2-((6-(Tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol- 99% MethodA 608 5-yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-1-yl)nicotinic 0.66mins acid

Tert-butyl 4-(3-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H- 17% MethodB 602 pyrazol-5-yl)amino)quinazolin-7-yl)oxy)propyl)piperazine-1- 1.06mins carboxylate

6-(Tert-butylsulfonyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)-7-(3- 98% MethodB 502 (piperazin-1-yl)propoxy)quinazolin-4-amine 0.84 mins

Methyl 6-(4-(3-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-   49.9%Method B 637 pyrazol-5-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-1.02 mins yl)nicotinate

6-(4-(3-((6-(Tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol- 99% MethodA 623 5-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1- 0.49 minsyl)nicotinic acid

Tert-butyl 4-(3-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H- 58% MethodA 601 pyrazol-5-yl)amino)quinazolin-7-yl)oxy)propyl)piperidine-1- 1.03mins carboxylate

6-(Tert-butylsulfonyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)-7-(3- 99% MethodA 501 (piperidin-4-yl)propoxy)quinazolin-4-amine 0.47 mins

Methyl 6-(4-(3-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H- 66% MethodB 636 pyrazol-5-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1- 1.19mins yl)nicotinate

6-(4-(3-((6-(Tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol- 96% MethodA 622 5-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1- 0.70 minsyl)nicotinic acid

Methyl 2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 71% MethodA 624 pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1- 0.60mins yl)pyrimidine-5-carboxylate

2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol- 98% MethodA 610.2 3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1- 0.52 minsyl)pyrimidine-5-carboxylic acid, 3 Hydrochloride

Methyl 2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 43% MethodA 637 pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1- 0.97yl)pyrimidine-5-carboxylate mins

2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol- 100% Method A 623 3-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1- 0.85mins yl)pyrimidine-5-carboxylic acid

Methyl 5-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 58% MethodB 624 pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1- 0.92yl)pyrazine-2-carboxylate mins

5-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol- 44% MethodB 610 3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1- 0.67 minsyl)pyrazine-2-carboxylic acid

Tert-butyl 4-((2-chloropyrimidin-5-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (561 mg,2.8 mmol) in THF (5 mL) was added 2-chloropyrimidin-5-ol (200 mg, 1.53mmol), triphenylphosphine (548 mg, 2.09 mmol) and DIAD (0.406 mL, 2.09mmol) and the reaction mixture was stirred at 20° C. under nitrogen for72 h. The reaction mixture was concentrated in vacuo, and the residuewas subjected directly to purification by flash chromatography (60 gpre-packed C-18 SNAP cartridge using a gradient elution from 35-90%acetonitrile (0.1% formic acid) in water (0.1% formic acid)). Desiredfractions were combined and concentrated to afford the title compound(430 mg, 1.1 mmol, 77% yield). LCMS RT=1.12 min, ES+ve 258 (M+H-tBu).

Tert-butyl4-((2-(4-(((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-5-yloxy)piperidine-1-carboxylate

To a solution of tert-butyl4-((2-chloropyrimidin-5-yl)oxy)piperidine-1-carboxylate (259 mg, 0.83mmol) in NMP (2 mL) was added DIPEA (0.6 mL, 3.4 mmol) and6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(piperidin-4-ylmethoxy)quinazolin-4-amine,3Hydrochloride (400 mg, 0.69 mmol) and the reaction mixture was stirredat 140° C. under an atmosphere of nitrogen for 42 h. The residue wassubjected directly to purification by flash chromatography (60 gpre-packed C-18 SNAP cartridge using a gradient elution from 50-95%acetonitrile (0.1% ammonia) in water (10 mM ammonium bicarbonate)).Desired fractions were combined and concentrated to afford the titlecompound (240 mg, 0.32 mmol, 47% yield). LCMS RT=1.09 min, ES+ve 750.

6-(Tert-butylsulfonyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)-7-((1-(5-(piperidin-4-yloxy)pyrimidin-2-yl)piperidin-4-yl)methoxy)quinazolin-4-amine

To tert-butyl4-((2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)piperidine-1-carboxylate(240 mg, 0.32 mmol) in DCM (2.0 mL) was added TFA (1.23 mL, 16 mmol) andthe reaction mixture was stirred at rt under nitrogen for 30 minutes.The mixture was evaporated to dryness to afford the title compound (350mg, 0.32 mmol, 99% yield). LCMS RT=0.57 min, ES+ve 650.

Tert-butyl((S)-1-(((S)-1-((S)-7-(2-(2-(2-(2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A mixture of4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-ol (61mg, 0.15 mmol), tert-butyl((S)-1-(((S)-1-((S)-7-(2-(2-(2-(2-chloroethoxy)ethoxy)ethoxy)ethoxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(80 mg, 0.098 mmol) and potassium carbonate (41 mg, 0.29 mmol) in DMF(1.5 mL) was heated at 105° C. for 8 hours. The crude product wassubjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound (78mg, 0.065 mmol, 67% yield). LCMS RT=1.11 min, ES+ve 1193.

Tert-butyl((S)-1-(((S)-1-((S)-7-(2-(2-(2-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3-(((R)-1,2,34-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A mixture of tert-butyl((S)-1-(((S)-1-((S)-7-(2-(2-(2-(2-chloroethoxy)ethoxy)ethoxy)ethoxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(800 mg, 0.98mmol),6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-ol(442 mg, 1.18 mmol), potassium carbonate (41 mg, 0.29 mmol) and sodiumiodide (147 mg, 0.98 mmol) in DMF (1.5 mL) was heated at 105° C. for 8hours. The cooled product mixture was filtered and subjected directly topurification by mass-directed automated preparative HPLC (formic acidmodifier) to afford the title compound (355 mg, 0.31 mmol, 31% yield)LCMS RT=1.21 min, ES+ve 1154.

Tert-butyl((S)-1-(((S)-1-((S)-7-((6-chloropyrimidin-4-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A solution of tert-butyl((S)-1-(((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(300 mg, 0.48 mmol) in DMF (7 mL) was treated with4,6-dichloropyrimidine (76 mg, 0.51 mmol) and potassium carbonate (147mg, 1.06 mmol) and then stirred at rt overnight. The mixture was treatedwith dichloromethane (30 mL) and water (10 mL). The organic phase wasevaporated to dryness and the product was purified by chromatography onsilica using a gradient elution from 0% to 100% ethyl acetate incyclohexane to afford the title compound (302 mg, 0.41 mmol, 85% yield).LCMS RT=1.46 min, ES+ve 733.

Tert-butyl((S)-1-(((S)-1-((S)-7-((6-(4-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-4-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A mixture of6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(piperidin-4-yloxy)quinazolin-4-amine(69 mg, 0.15 mmol) and tert-butyl((S)-1-(((S)-1-((S)-7-((6-chloropyrimidin-4-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(100 mg, 0.14 mmol) in DMF (2 mL) was treated with sodium bicarbonate(46 mg, 0.55 mmol) and stirred overnight at 100° C. The product wassubjected directly to purification by mass-directed automatedpreparative HPLC (ammonium bicarbonate modifier) to afford the titlecompound (92 mg, 0.08 mmol, 58% yield. LCMS RT=1.25 min, ES+ve 578([M+2H]2+).

Tert-butyl((S)-1-(((S)-1-((S)-7-((6-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-4-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

The title compound was prepared in a method analogous to that fortert-butyl((S)-1-(((S)-1-((S)-7-((6-(4-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-4-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate.42% yield. LCMS RT=1.25 min, ES+ve 585 ([M+2H]²⁺).

Tert-butyl((S)-1-(((S)-2-((2S,4S)-4-((2-chloropyrimidin-5-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Under an atmosphere of nitrogen, an ice-cooled solution of a mixture oftert-butyl((S)-1-(((S)-1-cyclohexyl-2-((2S,4R)-4-hydroxy-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(600 mg, 1.0 mmol), 2-chloropyrimidin-5-ol (161 mg, 1.2 mmol) andtriphenylphosphine (404 mg, 1.5 mmol) in tetrahydrofuran (15 mL) wastreated dropwise over 1 minute with DIAD (0.3 mL, 1.5 mmol). The mixturewas then stirred at room temperature for 6 hours and subsequentlytreated with dichloromethane (40 mL) and water (10 mL). The organicphase was evaporated to dryness and the product was purified bychromatography on silica using a gradient elution from 0-100% ethylacetate in cyclohexane followed by 0-5% methanol in ethyl acetate toafford the title compound (525 mg, 0.75 mmol, 73% yield). LCMS RT=1.38min, ES+ve 697.

Tert-butyl((S)-1-(((S)-2-((2S,4S)-4-((2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(piperidin-4-ylmethoxy)quinazolin-4-amine(41 mg, 0.086 mmol) in N-methyl-2-pyrrolidone (1 mL) was addedtert-butyl((S)-1-(((S)-2-((2S,4S)-4-((2-chloropyrimidin-5-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(60 mg, 0.086 mmol) and sodium bicarbonate (29 mg, 0.34 mmol). Thereaction mixture was heated to 100° C. for 18 hours then the product wassubjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound (43mg, 0.04 mmol, 44% yield). LCMS RT=1.27 min, ES+ve 567 ([M+2H]2+).

The following compounds were prepared in a method analogous to that fortert-butyl((S)-1-(((S)-2-((2S,4S)-4-((2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate:

Compound Name/Structure Yield LCMS RT ES +ve Tert-butyl((S)-1-(((S)-2-((2S,4S)-4-((2-(4-((6-(tert- 59% Method B 1119.4butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.44 minyl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-5-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-((2-(4-(2-((6-(tert- 40% Method A574.9 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.01 min [M + 2H]²⁺yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-((2-(4-(2-((6-(tert- 39% Method A574.4 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.29 min [M + 2H]²⁺yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-((2-(4-(3-((6-(tert- 41% Method A581.4 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.33 min [M + 2H]²⁺yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-1-((2S,4S)-4-((2-(4-(2-((6-(tert- 39% Method B1122.4 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.34 minyl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-1-((2S,4S)-4-((2-(4-(2-((6-(tert- 43% Method B1104.3 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.26 minyl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-2-((2,6-difluorophenyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

6-(Tert-butylsulfonyl)-7-(2-(2-chloroethoxy)ethoxy)-N-(4,5-dimethyl-1H-pyrazol-3-yl)quinazolin-4-amine

To a solution of6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-ol(50 mg, 0.13 mmol, obtained as described in WO 2014/128622) in DMSO (0.8mL) was added 1-chloro-2-(2-chloroethoxy)ethane (38.1 mg, 0.266 mmol),sodium iodide (2.0 mg, 0.013 mmol) and potassium carbonate (55 mg, 0.40mmol) and the reaction mixture was sealed and stirred at 80° C. in aBiotage microwave for 3 h. The product was subjected directly topurification by mass-directed automated preparative HPLC (formic acidmodifier) to afford the title compound (27 mg, 0.06 mmol, 42% yield).LCMS RT=0.72 min, ES+ve 482.

Tert-butyl((S)-1-(((S)-2-((2S,4S)-4-(5-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrazine-2-carboxamido)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

HATU (92 mg, 0.241 mmol) was added to a mixture of DIPEA (0.1 mL, 0.57mmol),5-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrazine-2-carboxylicacid (70 mg, 0.115 mmol) and tert-butyl((S)-1-(((S)-2-((2S,4S)-4-amino-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(78 mg, 0.13 mmol, obtained as described in WO 2014090709 A1) in DMF(0.55 mL). The reaction mixture was stirred at ambient temperature for1.5 h. The product was subjected directly to purification bymass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (74 mg, 0.06 mmol, 55% yield). LCMS Method BRT=1.32 min, ES+ve 1175.

The following compounds were prepared in a method analogous to that fortert-butyl((S)-1-(((S)-2-((2S,4S)-4-(5-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrazine-2-carboxamido)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate:

Compound Name/Structure Yield LCMS RT ES +ve Tert-butyl((S)-1-(((S)-2-((2S,4S)-4-(2-(4-(2-((6-(tert- 8% Method B 1175.36butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.34 minyl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carboxamido)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2- yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-(5-(4-(((6-(tert- 98% Method B1160.3 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.39 minyl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carboxamido)-2-(((R)-1,2,3,4-Tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-(6-(4-(3-((6-(tert- 97% Method B1188.69 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.47 minyl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)nicotinamido)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-(2-(4-(((6-(tert- 95% Method B1158.7 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.41 minyl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidine-5-carboxamido)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-(6-(4-(3-((6-(tert- 11% Method B1188.36 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.34 minyl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)nicotinamido)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-(2-(4-(2-((6-(tert- 47% Method B1201.32 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.22 minyl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carboxamido)-2-((3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-(2-(4-(3-((6-(tert- 21% Method B1215.20 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.50 minyl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carboxamido)-2-((3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((S)-1-((2S,4S)-4-(5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrazine-2-carboxamido)-2-((2,6-difluorophenyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl4-((S)-1-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)propanamido)-2-oxo-2-((S)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylate

A mixture of(S)—N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,Hydrochloride (68 mg, 0.24 mmol, obtained as described in patent WO2006/017295 A2) and(S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)propanamido)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)aceticacid (137 mg, 0.24 mmol, obtained as described in patent WO 2008/134679A1) in DMF (2 mL) was treated with DIPEA (0.085 mL, 0.48 mmol) followedby HATU (203 mg, 0.53 mmol). After 4 hr, the reaction was diluted withEtOAc (10 mL) and washed with water (2×10 mL) followed by brine (15 mL).The organic fraction was collected and concentrated in vacuo to obtainthe title product (176 mg, 0.22 mmol, 92% yield). LCMS RT method B RT1.47 min, ES+ve m/z 792

(9H-Fluoren-9-yl)methylmethyl((S)-1-oxo-1-(((S)-2-oxo-1-(piperidin-4-yl)-2-((S)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)ethyl)amino)propan-2-yl)carbamatehydrochloride

Tert-butyl4-((S)-1-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)propanamido)-2-oxo-2-((S)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylate(176 mg, 0.22 mmol) was treated with 4M HCl in dioxane (1 mL, 4 mmol).After 3 hr the reaction mixture was concentrated in vacuo to afford thetitle compound (160 mg, 0.22 mmol, 91% yield). LCMS RT (Method B) RT1.27 min, ES+ve m/z 692

(9H-Fluoren-9-yl)methyl((S)-1-(((S)-1-(1-(2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-oxo-2-((S)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carboxylicacid (126 mg, 0.21 mmol) and (9H-fluoren-9-yl)methylmethyl((S)-1-oxo-1-(((S)-2-oxo-1-(piperidin-4-yl)-2-((S)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)ethyl)amino)propan-2-yl)carbamate,Hydrochloride (151 mg, 0.21 mmol) were dissolved in DMF (1 mL). andtreated with DIPEA (0.144 mL, 0.83 mmol) and then with HATU (157 mg,0.41 mmol). After 2 hr the crude product was purified by mass-directedautomated preparative HPLC (ammonium bicarbonate modifier) to afford thetitle compound (40 mg, 0.031 mmol, 15% yield). LCMS Method B RT=1.29min, ES+ve 642 ([M+2H]2+).

(5S,8S,10aR)-methyl5-((tert-butoxycarbonyl)amino)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate

A mixture of (5S,8S,10aR)-methyl5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate(183 mg, 0.54 mmol, obtained as described in the patent WO 2011/050068A2) and5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carboxylicacid (213 mg, 0.36 mmol) were dissolved in DMF (2 mL) and treated withDIPEA (0.25 mL, 1.43 mmol) followed by HATU (163 mg, 0.43 mmol). After 1hr the crude reaction mixture was loaded directly onto a 60 g C18 columnand purified using a 5-70% acetonitrile in water (ammonium bicarbonatemodifier) to afford the title product (168 mg, 0.18 mmol, 51% yield)LCMS method B RT 1.08 min, ES+ve m/z 918.

(5S,8S,10aR)-Methyl5-amino-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate

(5S,8S,10aR)-Methyl5-((tert-butoxycarbonyl)amino)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylatewas treated with trifluoroacetic acid (4 mL). After 1 hr the reactionmixture was concentrated in vacuo and the residue was dissolved in MeOH(5 mL) and eluted through a 1 g amino propyl cartridge with methanol toafford the title compound (220 mg, 0.27 mmol, 75% yield). LCMS method BRT 0.89 min, ES+ve m/z 818

(5S,8S,10aR)-5-((S)-2-((Tert-butoxycarbonyl)(methyl)amino)propanamido)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylicacid

A mixture of (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid(57.4 mg, 0.28 mmol) and (5S,8S,10aR)-methyl5-amino-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate(220 mg, 0.27 mmol) in DMF (1.35 mL) was treated with DIPEA (0.188 mL,1.076 mmol) followed by HATU (112 mg, 0.30 mmol). After 4 hr 2M aqueousNaOH (3 mL, 6 mmol) was added. After a further 0.5 hr the reactionmixture was concentrated in vacuo, loaded on to a 60 g C18 column andpurified using a 5-60% gradient using acetonitrile/water (ammoniumbicarbonate modifier) to afford the title compound (105 mg, 0.11 mmol,40% yield). LCMS RT method B RT 0.82 min, ES+ve m/z 989.

Tert-butyl((S)-1-(((5S,8S,10aR)-8-(benzhydrylcarbamoyl)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A solution of(5S,8S,10aR)-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylicacid (40 mg, 0.04 mmol) and diphenylethanamine (8 μl, 0.044 mmol) in DMF(0.3 mL) was treated with DIPEA (0.021 mL, 0.12 mmol) followed by HATU(17 mg, 0.044 mmol). After 2 hr the crude product was purified bymass-directed automated preparative HPLC (ammonium bicarbonate modifier)to afford the title compound (24 mg, 0.021 mmol, 51% yield). LCMS methodB RT 1.26 min, ES+ve m/z 1155.

Using a method analogous to that for tert-butyl((S)-1-(((5S,8S,10aR)-8-(benzhydrylcarbamoyl)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamatethe following compound was prepared:

Compound Name/Structure Yield LCMS RT ES +ve Tert-butyl((S)-1-(((5S,8S,10aR)-3-(5-(4-(((6-(tert- 32% Method E 1118.3butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.21 minyl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-6-oxo-8-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((5S,8S,10aR)-3-(5-(4-(3-((6-(tert- 20% Method B1147.4 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.17 minyl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrazine-2-carbonyl)-6-oxo-8-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Tert-butyl ((S)-1-(((5S,8S,10aR)-3-(2-(4-(3-((6-(tert- 19% Method B573.5 butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3- 1.15 min (M + 2H)²⁺yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carbonyl)-6-oxo-8-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Example 1(S)-7-(2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-33-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,2Hydrochloride

A solution of tert-butyl((S)-1-(((S)-1-((S)-7-(2-(2-(2-(2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(65 mg, 0.055 mmol) in THF (1.5 mL) was treated with hydrochloric acid(4M in 1,4-dioxane) (3 mL, 12 mmol) and allowed to stand overnight. Thesolution was evaporated to dryness and the residual product wassubjected to purification by mass-directed automated preparative HPLC(ammonium bicarbonate modifier). The recovered material was dissolved inTHF (1 mL), treated with 1M HCl in 1,4-dioxane (0.5 mL), evaporated anddried under vacuum to afford the title compound (45 mg, 0.039 mmol, 71%yield). LCMS RT=0.72 min, ES+ve 1093.

Example 2(S)-7-(2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((S)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,2Hydrochloride

The title compound was prepared in a method analogous to that for(S)-7-(2-(2-(2-(2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,2Hydrochloride (Example 1) using(S)-1,2,3,4-tetrahydronaphthalen-1-amine in place of(R)-1,2,3,4-tetrahydronaphthalen-1-amine. LCMS RT=0.74 min, ES+ve 1093.

Example 3(S)-7-(2-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,2Hydrochloride

A solution of tert-butyl((S)-1-(((S)-1-((S)-7-(2-(2-(2-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(380 mg, 0.33 mmol) in dichloromethane (5 mL) was treated withtrifluoroacetic acid (5 mL) and stirred at ambient temperature for 30minutes. The mixture was evaporated to dryness; the residue was thendissolved in 4 mL of THF and treated with 4M HCl in 1,4-dioxan (5 mL).After 18 hours the resulting suspension was diluted with diethyl ether(10 mL) and filtered. The filtered solid was washed with diethyl etherand dried under vacuum to afford the title compound (277 mg, 0.25 mmol,75% yield). LCMS RT=1.17 min, ES+ve 1054.

The following compounds were prepared in a method analogous to that for(S)-7-(2-(2-(2-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,2Hydrochloride:

Compound Name/Structure Yield LCMS RT ES +ve Example 4  78% Method B1028 (2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert- 1.12 minbutylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-((R)-3-methylbutan-2-yl)pyrrolidine-2-carboxamide, 2 Hydrochloride

Example 5  90% Method B 1088(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert- 1.19 minbutylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide, 2 Hydrochloride

Example 6 100% Method B 1074(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert- 1.15 minbutylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-N-((R)-2,3-dihydro-1H-inden-1-yl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide, 2 Hydrochloride

Example 7 100% Method B 1076(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert- 1.18 minbutylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-((R)-1-phenylpropyl)pyrrolidine-2-carboxamide, 2 Hydrochloride

Example 8  99% Method B 1069(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert- 1.09 minbutylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-N-(2,6-difluorophenyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide, 2 Hydrochloride

Example 9(2S,4S)-4-(2-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,2 hydrochloride

A solution of tert-butyl((S)-1-(((S)-1-((2S,4S)-4-(2-(2-(2-(2-((6-(tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(68 mg, 0.06 mmol) in THF (0.5 mL) was treated with hydrochloric acid(4M in dioxan) (2 mL, 8 mmol). After 2 hours the mixture was evaporatedto dryness to afford the title compound (57 mg, 0.052 mmol, 86% yield).This was repurified by mass-directed automated preparative HPLC(ammonium bicarbonate modifier) to afford the free base which was takenup in THF (3 mL) and treated with 4M HCl in dioxan (0.5 mL) andevaporated to dryness to afford the title compound (28 mg, 0.03 mmol,42.2% yield). LCMS Method B RT=1.21 min, ES+ve 1031).

Example 10(2S,4S)-4-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)Pyrrolidine-2-carboxamide,2 Hydrochloride

Using a method analogous to that for(2S,4S)-4-(2-(2-(2-(2-((6-(tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,2 hydrochloride (Example 4) using 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl4-methylbenzenesulfonate in place of1-phenyl-2,5,8,11-tetraoxatridecan-13-yl 4-methylbenzenesulfonate, toafford the title compound (70 mg, 0.07 mmol, 96% yield). LCMS Method BRT=1.18 min, ES+ve 987).

Example 115-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,34-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide,3 Hydrochloride

A solution of tert-butyl((S)-1-(((S)-2-((2S,4S)-4-(5-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrazine-2-carboxamido)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(74 mg, 0.063 mmol) in DCM (2 mL) was treated with hydrochloric acid (4Min 1,4-dioxane) (0.9 mL, 3.6 mmol) and the mixture was stirred atambient temperature for 1 h. The mixture was removed of solvent in vacuoto afford the title compound (70 mg, 0.06 mmol, 91% yield). LCMS MethodB RT=1.12 min, ES+ve 1075.

The following compounds were prepared using a method analogous to thatfor5-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide,3 Hydrochloride:

Compound Name/Structure Yield LCMS RT ES +ve Example 12 100% Method B1075.4 2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 1.15 minpyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide hydrochloride

Example 13  98% Method B 1060.375-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol- 1.19 min3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide

Example 14  97% Method B 1087.46-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 1.28 minpyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3- yl)nicotinamide

Example 15  95% Method B 1060.42-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol- 1.23 min3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide

Example 16  94% Method B 1088.346-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 1.15 minpyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3- yl)nicotinamide

Example 17 100% Method B 1089.385-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 1.15 minpyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide

Example 18 100% Method B 1064.412-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 1.15 minpyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide

Example 19  10% Method B 1063.465-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 1.11 minpyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide

Example 20  99% Method B 1049.37(2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5- 1.12 mindimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2- carboxamide,4hydrochloride

Example 21 100% Method B 1045.352-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 1.02 minpyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide

Example 22  59% Method B 1101.32-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 1.03 minpyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5- carboxamide

Example 23  97% Method B 1115.42-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H- 1.04 minpyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5- carboxamide

Example 24(S)-7-((6-(4-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-4-yloxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

A solution of tert-butyl((S)-1-(((S)-1-((S)-7-((6-(4-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-4-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(70 mg, 0.061 mmol) in dichloromethane (3 mL) was treated withtrifluoroacetic acid (1 mL) and the mixture stirred for 15 minutes. Themixture was evaporated to dryness, treated with DMSO (1.5 mL) and DIPEA(0.5 mL) and then the product was subjected to purification bymass-directed automated preparative HPLC (ammonium bicarbonate modifier)to afford the title compound (46 mg, 0.04 mmol, 72% yield). LCMS RT=1.23min, ES+ve 1055.

Example 25(S)-7-((6-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-4-yl)oxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

The following compound was made using a method analogous to that for(S)-7-((6-(4-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-4-yl)oxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide:

74% yield. LCMS RT=1.26 min, ES+ve 1069.

Example 26(2S,4S)-4-((2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,34-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,4Hydrochloride

A solution of tert-butyl((S)-1-(((S)-2-((2S,4S)-4-((2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(58 mg, 0.051 mmol) in THF (2 mL) was treated with hydrochloric acid (4M in dioxane) (2 mL, 8 mmol) and the mixture was stirred at ambienttemperature for 2 hours. The mixture was evaporated to dryness to affordthe title compound (56 mg, 0.05 mmol, 93% yield). LCMS Method B RT=1.27min, ES+ve 1033.

The following compounds were prepared in an analogous manner to(2S,4S)-4-((2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,4Hydrochloride using the appropriate amine starting material:

Compound Name/Structure Yield LCMS RT ES +ve Example 27 93% Method B1019 (2S,4S)-4-((2-(4-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl- 1.25min 1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-(R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide, 4Hydrochloride

Example 28 94% Method B 1048(2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5- 1.20 mindimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2- carboxamide,4Hydrochloride

Example 29 96% Method B 1047(2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5- 1.30 mindimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2- carboxamide,4Hydrochloride

Example 30 91% Method B 1061(2S,4S)-4-((2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5- 1.34 mindimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2- carboxamide,4Hydrochloride

Example 31 77% Method B 1022.4(2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl- 1.11 min1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide hydrochloride

Example 32 20% Method B 1004(2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl- 1.04 min1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-N-(2,6-difluorophenyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide hydrochloride

Example 33 38% Method B 1031.492-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol- 1.02 min3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide

Example 34 26% Method B 1045.325-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol- 1.00 min3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide

Example 35(S)-1-((S)-2-(1-(2-(4-(2-((6-(Tert-butylsulfonyl-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide

(9H-Fluoren-9-yl)methyl((S)-1-(((S)-1-(1-(2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-oxo-2-((S)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(40 mg, 0.031 mmol) was dissolved in tetrahydrofuran (2 mL) and treatedwith piperidine (3 mL, 30 mmol). After 1 hr, the reaction wasconcentrated in vacuo and purified by mass-directed automatedpreparative HPLC (ammonium bicarbonate modifier) to afford the titlecompound (26 mg, 0.024 mmol, 12% yield). LCMS Method B RT=0.98 min,ES+ve 1061.

LCMS RT Compound Name/Structure Yield (mins) ES +ve Example 36 11%Method B 1075.35(S)-1-((S)-2-(1-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5- 1.00 mindimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-((S)-2-(methylamino)propanamido)acetyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamidc

Example 37(5S,8S,10aR)—N-Benzhydryl-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

Tert-butyl((S)-1-(((5S,8S,10aR)-8-(benzhydrylcarbamoyl)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(24 mg, 0.021 mmol) was treated with trifluoroacetic acid (1 mL). After1 hr the reaction mixture was concentrated in vacuo and the residuedissolved in methanol (5 mL) and passed through a 500 mg amino propylcartridge eluting with methanol. The resultant product-containingfraction was evaporated to dryness to obtain the title compound (20 mg,0.019 mmol, 47% yield). LCMS Method B RT 1.09 min, ES+ve m/z 1055

The following compound was prepared in a method analogous to that for(5S,8S,10aR)-N-benzhydryl-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide:

Compound Name/Structure Yield LCMS RT ES +ve Example 38 98% Method B1019.34 (5S,8S,10aR)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5- 1.04 mindimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

Example 39 99% Method B 1047.52(5S,8S,10aR)-3-(5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5- 1.00 mindimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

Example 40 99% Method B 1045.36(5S,8S,10aR)-3-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5- 1.01 mindimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

Western Blot Quantification of RIP2 Levels in THP1 Cells

Compounds were tested in THP1 cells (acute myeloid leukaemia—BioCat106491) and the effect on RIP2 protein levels were assessed by Westernblotting. For each sample 7.5×10⁶ cells were resuspended in mediacontaining the indicated concentrations of PROTAC and incubated 37° C.and 5% CO₂ overnight. The following day, cells were harvested, and thetotal amount of protein was quantified using the Pierce™ BCA ProteinAssay kit (Thermo Scientific, 23227). 25 μg of total protein wereseparated on a polyacrylamide Bis-Tris gel at constant voltage andfurther transferred onto PVDF membranes (Millipore, IPFL00010).Membranes were blocked against non-specific binding with Odysseyblocking buffer (Licor, 927-40000) for 1 hour at room temperature, thenincubated with the primary antibodies rabbit anti-RIPK2 (Cell Signaling,4142) overnight at 4° C. Next day the mouse anti-actin (Sigma, A2228) ata 1:20 000 dilution was added and the membranes were further incubatedfor 2 hours at room temperature. Membranes were washed 3 times withPBS+0.1% Tween 20 then incubated with donkey anti-mouse 800CW (Licor,926-32212) and donkey anti-mouse IRdye 680RD (Licor, 926-68072) diluted1:5 000 in Odyssey blocking buffer+0.1% Tween 20+0.01% SDS, 1 hour atroom temperature, followed by washing in PBS+0.1% Tween 20. The infraredsignal was detected using an Odyssey scanner (Licor Biosciences) anddensitometry was performed using the Odyssey 2.1 Analyser software(Licor Biosciences).

RIPK2 degradation was expressed relative to the DMSO only treatedsample. Compounds displayed >80% degradation of RIP2 at concentrations<1 uM.

1. A method of treating diseases and conditions mediated by the RIP2Kinase in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I):

wherein X represents N or CH; L is a linking group comprising a lengthof 4-16 atoms in shortest length, R¹ is H, —SO₂(C₁-C₄)alkyl,—CO(C₁-C₄)alkyl, or (C₁-C₄)alkyl; R² is —SR^(a), —SOR^(a), —SO₂R^(a),—SO₂NH₂, or —SO₂NR^(b)R^(c), wherein R^(a) is (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₂)cycloalkyl, 4-7 membered heterocycloalkyl,aryl, or heteroaryl, wherein: said (C₁-C₆)alkyl is optionallysubstituted by one or two groups each independently selected from thegroup consisting of cyano, hydroxyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₂-C₆)alkoxy, —CO₂H, —CO₂(C₁-C₄)alkyl, —SO₂(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 memberedheteroaryl, 4-7 membered heterocycloalkyl and (phenyl)(C₁-C₄alkyl)amino-, wherein said (C₃-C₇)cycloalkyl, phenyl, (phenyl)(C₁-C₄alkyl)amino-, 5-6 membered heteroaryl, 9-10 membered heteroaryl or 4-7membered heterocycloalkyl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of halogen, —CF₃,hydroxyl, amino, ((C₁-C₄)alkyl)amino-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl and (C₁-C₄)alkoxy, said (C₃-C₇)cycloalkyl or 4-7membered heterocycloalkyl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of halogen, —CF₃,hydroxyl, amino, ((C₁-C₄)alkyl)amino-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl-, oxo and (C₁-C₄)alkoxy, and said aryl or heteroarylis optionally substituted by 1-3 groups each independently selected fromthe group consisting of halogen, —CF₃, hydroxyl, amino,((C₁-C₄)alkyl)amino-, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-, (C₁-C₄)alkyl,phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl- and (C₁-C₄)alkoxy; R^(b) is(C₁-C₆)alkyl or 4-7 membered heterocycloalkyl, wherein: said(C₁-C₆)alkyl is optionally substituted by one or two groups eachindependently selected from the group consisting of hydroxyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₂-C₆)alkoxy, —CO₂H, —CO₂(C₁-C₄)alkyl,(C₁-C₄ alkyl)amino-, (C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl, wherein said 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by1-3 groups each independently selected from the group consisting ofhalogen, (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl and (C₁-C₄)alkoxy, said 4-7membered heterocycloalkyl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of hydroxyl, amino,(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl-, hydroxy(C₁-C₄)alkyl-, oxo and(C₁-C₄)alkoxy, and R^(c) is H, (C₁-C₄)alkoxy or (C₁-C₆)alkyl; or R^(b)and R^(c) taken together with the nitrogen atom to which they areattached form a 3-7 membered heterocycloalkyl group, optionallycontaining one or two additional ring heteroatoms each independentlyselected from nitrogen and oxygen, wherein said 3-7 memberedheterocycloalkyl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of (C₁-C₄)alkyl,hydroxy, —CO₂H and —CO(C₁-C₄)alkyl; Z is phenyl or aryl(C₁-C₄)alkyl-,wherein in the phenyl group or the aryl moiety of the aryl(C₁-C₄)alkyl-group is substituted by R⁴, R⁵, R⁶ and R⁷, wherein: R⁴ is H, halogen,cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy,phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, or aminocarbonyl,wherein the phenyl moiety of said phenoxy or phenyl(C₁-C₄)alkoxy- isoptionally substituted by 1-3 substituents each independently selectedfrom the group consisting of halogen, —CF₃, (C₁-C₄)alkyl and(C₁-C₄)alkoxy; and each of R⁵, R⁶ and R⁷ is independently selected fromthe group consisting of H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; or Z is phenyl or pyridyl, substitutedby R⁸, R⁹ and R¹⁰, wherein: R⁸ and R⁹ are located on adjacent atoms andtaken together with the atoms to which they are attached form a5-membered ring containing 1, 2 or 3 heteroatoms each independentlyselected from N, O and S, which 5-membered ring is substituted by R¹¹;wherein one of R¹⁰ or R¹¹ is H, halogen, cyano, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, or aminocarbonyl, where the phenyl moiety of saidphenoxy or phenyl(C₁-C₄)alkoxy is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy; and the other of R¹⁰ orR¹¹ is H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl or(C₁-C₄)alkoxy; or Z is pyrazolyl, having the formula:

wherein: R¹² is H, methyl or hydroxymethyl; R¹³ is methyl,trifluoromethyl or hydroxymethyl; R¹⁴ is H, OH, or (C₁-C₃)alkyl; or R¹²and R¹³, taken together with the atoms to which they are attached, forma 6-membered ring substituted by R¹⁵ and R¹⁶, wherein the 6-memberedring optionally contains 1 nitrogen atom; wherein R¹⁵ and R¹⁶ are eachindependently selected from the group consisting of H, halogen, cyano,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy,phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, and aminocarbonyl,wherein the phenyl moiety of said phenoxy or phenyl(C₁-C₄)alkoxy isoptionally substituted by 1-3 substituents each independently selectedfrom the group consisting of halogen, —CF₃, (C₁-C₄)alkyl and(C₁-C₄)alkoxy; or a pharmaceutically acceptable salt thereof.
 2. Amethod of treating diseases and conditions mediated by the RIP2 Kinasecomprising administering to a human in need thereof a therapeuticallyeffective amount of a combination comprising compound of formula (I):

wherein X represents N or CH; L is a linking group comprising a lengthof 4-16 atoms in shortest length, R¹ is H, —SO₂(C₁-C₄)alkyl,—CO(C₁-C₄)alkyl, or (C₁-C₄)alkyl; R² is —SR^(a), —SOR^(a), —SO₂R^(a),—SO₂NH₂, or —SO₂NR^(b)R^(c), wherein R^(a) is (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 4-7 membered heterocycloalkyl,aryl, or heteroaryl, wherein: said (C₁-C₆)alkyl is optionallysubstituted by one or two groups each independently selected from thegroup consisting of cyano, hydroxyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₂-C₆)alkoxy, —CO₂H, —CO₂(C₁-C₄)alkyl, —SO₂(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 memberedheteroaryl, 4-7 membered heterocycloalkyl and (phenyl)(C₁-C₄alkyl)amino-, wherein said (C₃-C₇)cycloalkyl, phenyl, (phenyl)(C₁-C₄alkyl)amino-, 5-6 membered heteroaryl, 9-10 membered heteroaryl or 4-7membered heterocycloalkyl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of halogen, —CF₃,hydroxyl, amino, ((C₁-C₄)alkyl)amino-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl and (C₁-C₄)alkoxy, said (C₃-C₇)cycloalkyl or 4-7membered heterocycloalkyl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of halogen, —CF₃,hydroxyl, amino, ((C₁-C₄)alkyl)amino-,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-, (C₁-C₄)alkyl, phenyl(C₁-C₄)alkyl-,hydroxy(C₁-C₄)alkyl-, oxo and (C₁-C₄)alkoxy, and said aryl or heteroarylis optionally substituted by 1-3 groups each independently selected fromthe group consisting of halogen, —CF₃, hydroxyl, amino,((C₁-C₄)alkyl)amino-, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino-, (C₁-C₄)alkyl,phenyl(C₁-C₄)alkyl-, hydroxy(C₁-C₄)alkyl- and (C₁-C₄)alkoxy; R^(b) is(C₁-C₆)alkyl or 4-7 membered heterocycloalkyl, wherein: said(C₁-C₆)alkyl is optionally substituted by one or two groups eachindependently selected from the group consisting of hydroxyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₂-C₆)alkoxy, —CO₂H, —CO₂(C₁-C₄)alkyl,(C₁-C₄ alkyl)amino-, (C₁-C₄ alkyl)(C₁-C₄ alkyl)amino-, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl, wherein said 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by1-3 groups each independently selected from the group consisting ofhalogen, (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl and (C₁-C₄)alkoxy, said 4-7membered heterocycloalkyl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of hydroxyl, amino,(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl-, hydroxy(C₁-C₄)alkyl-, oxo and(C₁-C₄)alkoxy, and R^(c) is H, (C₁-C₄)alkoxy or (C₁-C₆)alkyl; or R^(b)and R^(c) taken together with the nitrogen atom to which they areattached form a 3-7 membered heterocycloalkyl group, optionallycontaining one or two additional ring heteroatoms each independentlyselected from nitrogen and oxygen, wherein said 3-7 memberedheterocycloalkyl is optionally substituted by 1-3 groups eachindependently selected from the group consisting of (C₁-C₄)alkyl,hydroxy, —CO₂H and —CO(C₁-C₄)alkyl; Z is phenyl or aryl(C₁-C₄)alkyl-,wherein in the phenyl group or the aryl moiety of the aryl(C₁-C₄)alkyl-group is substituted by R⁴, R⁵, R⁶ and R⁷, wherein: R⁴ is H, halogen,cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy,phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, or aminocarbonyl,wherein the phenyl moiety of said phenoxy or phenyl(C₁-C₄)alkoxy- isoptionally substituted by 1-3 substituents each independently selectedfrom the group consisting of halogen, —CF₃, (C₁-C₄)alkyl and(C₁-C₄)alkoxy; and each of R⁵, R⁶ and R⁷ is independently selected fromthe group consisting of H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkyl and (C₁-C₄)alkoxy; or Z is phenyl or pyridyl, substitutedby R⁸, R⁹ and R¹⁰, wherein: R⁸ and R⁹ are located on adjacent atoms andtaken together with the atoms to which they are attached form a5-membered ring containing 1, 2 or 3 heteroatoms each independentlyselected from N, O and S, which 5-membered ring is substituted by R¹¹;wherein one of R¹⁰ or R¹¹ is H, halogen, cyano, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy, phenyl(C₁-C₄)alkoxy, hydroxyl,hydroxy(C₁-C₄)alkyl-, or aminocarbonyl, where the phenyl moiety of saidphenoxy or phenyl(C₁-C₄)alkoxy is optionally substituted by 1-3substituents each independently selected from the group consisting ofhalogen, —CF₃, (C₁-C₄)alkyl and (C₁-C₄)alkoxy; and the other of R¹⁰ orR¹¹ is H, hydroxyl, halogen, —CF₃, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl or(C₁-C₄)alkoxy; or Z is pyrazolyl, having the formula:

 wherein: R¹² is H, methyl or hydroxymethyl; R¹³ is methyl,trifluoromethyl or hydroxymethyl; R¹⁴ is H, OH, or (C₁-C₃)alkyl; or R¹²and R¹³, taken together with the atoms to which they are attached, forma 6-membered ring substituted by R¹⁵ and R¹⁶, wherein the 6-memberedring optionally contains 1 nitrogen atom; wherein R¹⁵ and R¹⁶ are eachindependently selected from the group consisting of H, halogen, cyano,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, phenoxy,phenyl(C₁-C₄)alkoxy, hydroxyl, hydroxy(C₁-C₄)alkyl-, and aminocarbonyl,wherein the phenyl moiety of said phenoxy or phenyl(C₁-C₄)alkoxy isoptionally substituted by 1-3 substituents each independently selectedfrom the group consisting of halogen, —CF₃, (C₁-C₄)alkyl and(C₁-C₄)alkoxy; or a pharmaceutically acceptable salt thereof, and atleast one further therapeutic agent.
 3. The method of claim 1 whereinthe compound is a compound of Formula (II), (III), or (IV):

In particular, the definitions of R¹, Z, X and R² in the RIP2 inhibitormoiety in the compounds of formula (II) and (III) are as defined inclaim 1 above. The linker is as defined for claim 1 For the IAP bindingmoiety, in formula (II) and (III) R¹ and R² are independently optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted arylalkyl,optionally substituted aryl, or R¹ and R² are independently optionallysubstituted thioalkyl wherein the substituents attached to the S atom ofthe thioalkyl are optionally substituted alkyl, optionally substitutedbranched alkyl, optionally substituted heterocyclyl, —(CH2)vCOR₂₀,—CH2CHR₂₁COR₂₂ or —CH₂R₂₃. Wherein v-1-3, R₂₀ and R₂₂ are independentlyselected from OH, NR₂₄ R₂₅ or OR₂₆, R₂₁ is NR₂₄R₂₅, R23 is optionallysubstituted aryl or optionally substituted heterocyclyl, where theoptional substituents include alkyl and halogen, R₂₄ is hydrogen oroptionally substituted alkyl, R₂₅ is hydrogen, optionally substitutedalkyl, optionally substituted branched alkyl, optionally substitutedarylalkyl, optionally substituted heterocyclyl, —CH2(OCH₂CH₂O)_(m)CH₃,or a polyamine chain, R₂₆ is optionally substituted alkyl, w=1-8, Wherethe optional substituents are OH, halogen or NH₂; R³ and R⁴ areindependently optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted arylalkoxy, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedheteroarylalkyl or optionally substituted hetercycloalkyl, wherein thesubstitutents are alkyl, halogen or OH; R₅, R⁶, R⁷ and R⁸ areindependently hydrogen, optionally substituted alkyl or optionallysubstituted cycloalkyl; R⁹ is hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl or CO alkyl;

In particular, the definitions of R¹, Z, X and R² in the RIP2 inhibitormoiety in the compounds of formula (IV) are as defined in claim 1 Thelinker is as defined in claim 1 For the IAP binding moiety, in formula(IV) R is selected from the group consisting of

wherein ring A is C₄₋₈ aliphatic ring,

wherein the B ring is aryl or nitrogen atom-containing heteroaryl andthe B rings are optionally substituted; or a pharmaceutically acceptablesalt thereof.
 4. The method according to claim 3 wherein in formula IVring B is phenyl, napthyl, pyridinyl, pyrazonyl or pyrimidinyl
 5. Themethod according to claim 1 wherein the linker is a straight chainalkyline group of 4-20 carbon atoms wherein one or more carbo atoms isreplaced by a group each independently selected from —O—, —NH—, —N(CH₃),—CO—, piperidine, piperazine, pyrimidine, pyridine and phenyl.
 6. Themethod according to claim 1 wherein the linker is (in the direction RIP2Kinase inhibitor—IAP inhibitor— O(CH₂CH₂O)₃₋₄ O(ch₂ch₂)₄ OCH₂CONH

wherein X is O(CH₂CH₂)₀₋₄ and Y is CONH, O or CO
 7. The method accordingto claim 1 wherein the linker is (in the one linker RIP2 Kinaseinhibitor—IAP inhibitor (OCH₂CH₂)₄O— (OCH₂CH₂)₃O— (OCH₂CH₂)₄OCH₂CONH


8. The method according to claim 1 wherein the compound of Formula (I)is:S)-7-(2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,(S)-7-(2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((S)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,(S)-7-(2-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-t((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-3-methylbutan-2-yl)pyri(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-N—((R)-2,3-dihydro-1H-inden-1-yl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide,(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1-phenylpropyl)pyrrolidine-2-carboxamide,(2S,4S)-4-(14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12-tetraoxatetradecanamido)-N-(2,6-difluorophenyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide,(2S,4S)-4-(2-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide;(2S,4S)-4-(2-(2-(2-((6-(Tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,5-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide,2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide;6-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)nicotinamide;2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;6-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)nicotinamide;5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide;2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide;(2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;(S)-7-((6-(4-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-4-yl)oxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;(S)-7-((6-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-4-yl)oxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;(2S,4S)-4-((2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,(2S,4S)-4-((2-(4-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,(2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,(2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,(2S,4S)-4-((2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide,(2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide(2S,4S)-4-((2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-N-(2,6-difluorophenyl)-1-((S)-3,3-dimethyl-2-((S)-2(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrimidine-5-carboxamide;5-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-((3S,5S)-5-((2,6-difluorophenyl)carbamoyl)-1-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidin-3-yl)pyrazine-2-carboxamide(S)-1-((S)-2-(1-(2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-((S)-2-(methylamino)propanamido)acetyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide;(S)-1-((S)-2-(1-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolinyl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-((S)-2-(methylamino)propanamido1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide;(5S,8S,10aR)—N-Benzhydryl-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide;(5S,8S,10aR)-3-(5-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide;(5S,8S,10aR)-3-(5-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrazine-2-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide;(5S,8S,10aR)-3-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)pyrimidine-5-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide;and pharmaceutically acceptable salts thereof